CN1454083A - 选择性雄激素受体调节剂及其鉴定、设计和应用的方法 - Google Patents
选择性雄激素受体调节剂及其鉴定、设计和应用的方法 Download PDFInfo
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Abstract
本发明提供选择性雄激素受体调节剂(SARM),该调节剂对激素依赖性肿瘤具有拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或呈现激动活性,还提供鉴定、设计和应用SARM的方法。
Description
本申请要求以下申请的优先权:2000年6月28日申请的美国临时专利申请序列号60/214,392、2000年9月19日申请的美国临时专利申请序列号60/233,519、2001年4月18日申请的美国临时专利申请序列号60/284,617、2001年4月18日申请的美国临时专利申请序列号60/284,438、2001年4月18日申请的美国临时专利申请序列号60/284,730,各内容全部结合到本发明中作为参考。
发明领域
已证实选择性雄激素受体调节剂(SARM)对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动剂活性。本发明涉及应用这些SARM在治疗可通过给予雄激素受体调节剂治愈的病症上的方法。本发明还涉及设计和鉴别新SARM的方法,这些SARM对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动剂活性。本发明还涉及雄激素受体配体结合结构域或配体结合结构域复合物的结构配位,以及应用这些结构配位设计和选择调节雄激素受体的新SARM的方法。
发明背景
雄激素受体(AR)是配体依赖性转录因子的甾体核-受体超家族的成员,其广泛分布于增殖和非增殖组织,包括前列腺和精囊、雄性和女性生殖器、皮肤、睾丸、卵巢、软骨、皮脂腺、毛囊、汗腺、心肌、骨骼和平滑肌、胃肠道囊状细胞、甲状腺滤泡细胞、肾上腺皮质、肝脏、松果体和多个大脑皮质区及皮质下区,包括脊髓运动神经元(Negro-Vilar,A.JCE&M 1999 54(10):3459-62)。与该甾体受体家族的其它成员一样,AR具有数个功能结构域,包括DNA结合结构域(DBD)和包含雄激素结合结构域的261个残基的配体结合结构域(LBD)(Mw=30,245Da),该结合结构域具有接通雄激素功能的作用。人和大鼠雄激素受体的cDNA和氨基酸序列已有报导(Proc.Natl.Acad.Sci.U.S.A.1988 85:7211-7215)。
在药物发现和患者疗法的多个领域中,AR是重要的目标。在肿瘤学中,例如,雄激素受体功能的抑制剂(拮抗剂或部分拮抗剂)可用于治疗雄激素依赖性前列腺癌,而AR的激动剂或部分激动剂用于治疗乳腺癌。对于代谢和内分泌性疾病,例如雄激素受体功能的激动剂或部分激动剂用于治疗与年龄有关的疾病和数种病态中的恶质病病症,包括但不限于AIDS。已在多种骨细胞中证实了功能性AR,服用雄激素有盖于男女的骨骼生长和维持。
雄激素疗法的发展一直受到不能够将所要求的雄激素活性与不合要求的或剂量限定的副作用分开的限制。但是,近来在研制选择性雌激素受体调节剂(SERM)上的进展为SARM(即选择性雄激素受体调节剂)给出提示,所述SERM靶向雌激素受体时具有高度组织选择性,同时消除不良副作用(Negro-Vilar,A.JCE&M 1999 54(10):3459-62;Reid等,Investigational New Drugs 1999 17:271-284)。
美国专利6,017,924基于“顺式-反式”或“共转染”测定,公开了特征在于对雄激素受体具有高度的亲和力、高特异性激动剂、部分激动剂(即部分激活剂和/或组织特异性激活剂)和拮抗剂的非甾体化合物。通过“顺式-反式”或“共转染”测定,确定的特征在于对雄激素受体具有高度的亲和力、高特异性激动剂、部分激动剂(即部分激活剂和/或组织特异性激活剂)和拮抗剂的非甾体化合物还在WO01/16108、WO 01/16133和WO 01/16139中公开。现认为这种共转染测定(Evans等,Science 1988 240:889-95)为鉴定模拟天然激素功能的功能性激动剂或部分激动剂或者抑制天然激素功能的拮抗剂提供了方法,并为定量测定敏感细胞内受体蛋白的活性提供了方法。
另外,已认为羟基氟他胺,即一种已知的多种组织AR拮抗剂,可作为一种选择性AR调节剂(SARM),通过成骨细胞影响IL-6的产生(Hofbauer等,J.Bone Miner.Res,1999 14:1330-1337)。
羟基氟他胺和卡索地司都是已知的多种组织完全AR拮抗剂,现已表明在AR-转染的PC3细胞中,其能以类似于DHT的AR依赖性方式激活MAP激酶Erk-1和Erk-2(Peterziel等,Oncogene 18:6322-6329(1999))。
化合物LGD2226是一种非甾体AR激动剂,也可作为选择性雄激素受体调节剂,用于治疗与雄激素有关的疾病,如骨质疏松症、雄性激素替代、雄性或雌性性功能失调和恶质病(SCRIP-WorldPharmaceutical New FILED 12 May 2000;WO 01/16108;WO01/16133;和WO 01/16139)。
化合物LG120907是一种非甾体AR激动剂,已表明在大鼠中,与其它临床上所用的AR拮抗剂(卡索地司)相比,其对下丘脑轴和对性欲(繁殖率)的拮抗活性降低。因此LG120907可作为选择性雄激素受体调节剂,用于治疗前列腺癌(Wang等,Poster #P3-126,EndocrineSociety 80th Annual Meeting(1998),Hamann等,Presentation #S39-2,Endocrine Society 80th Annual Meeting(1998))。
最近对甾体性激素(如DHT和E2)对AR和ER的非基因性作用的研究报告清楚表明:两种受体均调节非特异性参与转录有关的功能(Kousteni等,Cell 104,719-730(2001))。已表明ER和AR的抗凋亡作用是由对转录无作用的配体诱发。还表明:对转录有影响的受体不具有抗凋亡作用。
相对于含有雄激素受体的其它非肿瘤组织,对含有雄激素受体的肿瘤组织呈现出调节作用差别的SARM(尤其是对肿瘤具有拮抗活性,而对含雄激素受体的其它非肿瘤组织呈现激动活性),目前既没有公开也没有暗示性公开。本发明提供SARM以及鉴别和设计这些SARM的方法,该SARM对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性。如下所述,例如,可用这些SARM通过抑制肿瘤的生长,同时减轻副作用,如肌肉消瘦/恶质病、失去性欲、骨质疏松症和男子女性型乳房,从而治疗患者的激素依赖性肿瘤(如前列腺癌)。本文所用术语“患者”指动物,优选哺乳动物,如狗、猫,或者最优选人。
发明概述
本发明的一个目的是提供鉴别SARM的方法,该SARM对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性。在一个实施方案中,通过筛选体外或体内对激素依赖性肿瘤细胞系的生长抑制作用,确定对激素依赖性肿瘤细胞的拮抗活性。在该实施方案中,还可用正常非肿瘤细胞系确定潜在SARM的活性。另外,可用带有激素依赖性肿瘤的动物模型确定潜在SARM对肿瘤的拮抗活性以及对动物非肿瘤组织的活性。
本发明另一目的通过利用AR晶体结构和雌二醇、他莫昔芬或雷洛昔芬的雌激素受体(ER)晶体结构信息,提供设计SARM的方法,该SARM对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性。
本发明另一目的提供用于鉴定SARM的分子或分子复合物,其包含表A中雄激素受体配体结合结构域(AR-LBD)氨基酸V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907的结构配位定义的所有或任何部分的该配体结合位点,或者所述分子或分子复合物的突变体或同系物。
本发明另一目的提供机器可读数据储存介质,其包括机器可读数据编码的数据贮存材料,其中该数据由表A中AR-LBD与AR-LBD配体或配体复合物或者该复合物的同系物的结构配位限定,其中该同系物包含与所述复合物主链原子的均方根偏差不超过3.0埃的主链原子。
本发明另一目的提供用于AR调节剂的AR-LBD的结合部位点,其中该配体的一部分与表A中AR-LBD的任何部分或所有的残基V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907以范德华力接触或氢键接触。在一个优选实施方案中,该结合部位是与本文所提供的表A中的AR-LBD的残基V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907具有25%-95%同一性的同系物或突变体。
本发明另一目的提供对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性的SARM,以及包含至少一种这样SARM和药学上可接受的载体的药用组合物。在一个优选实施方案中,根据本发明方法鉴定或设计该SARM。
本发明另一目的提供一种抑制激素依赖性肿瘤细胞生长的方法,该方法包括使该肿瘤细胞与SARM接触,其中SARM对该激素依赖性肿瘤呈现拮抗作用,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性。
除非另有说明外,否则可将对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性的本发明SARM设想在本发明的所有实施方案中还对正常前列腺组织具有激动剂、拮抗剂或无活性。
本发明再一目的提供通过给予本文所述的雄激素受体调节剂,应用这些SARM治疗可治愈的病症的方法,其中该病症包括但不限于女性多毛症(hirsutism)、痤疮、皮脂溢、阿尔茨海默氏病、雄激素性脱发、性腺机能减退、多毛症(hyperpilosity)、良性前列腺肥大、前列腺瘤(如晚期转移前列腺癌)、含雄激素受体的良性或恶性肿瘤细胞的治疗,例如乳腺、大脑、皮肤、卵巢、膀胱、淋巴、肝和肾癌、胰癌、调节VEGF表达及其用作抗血管发生剂的各种应用、骨质疏松症、抑制精子生成、性欲、恶质病、子宫内膜异位症、多囊卵巢综合症、厌食症、雄激素依赖性的年龄相关性疾病和病症,例如男性年龄相关性睾丸素水平降低的雄激素补充、雄性绝经、雄性激素替代、雄性或雌性性功能障碍以及抑制非卧床患者的肌肉萎缩。特别优选应用SARM治疗激素依赖性肿瘤,尤其是早期前列腺癌,以及化学预防激素依赖性癌症,尤其是前列腺癌。
本发明参考的所有文献,包括但不限于美国专利申请,都全部结合到本发明中作为参考。发明详述
现已证实选择性雄激素受体调节剂(SARM)对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它(一种或多种)非肿瘤组织无活性或更优选呈现激动活性。对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性的本发明SARM还被称为特异性雄激素受体调节剂。
本发明的“非肿瘤”、“非癌”或“非恶性”的含雄激素受体的组织包括但不限于精囊、雄性和雌性生殖器、皮肤、睾丸、卵巢、软骨、皮脂腺、毛囊、汗腺、肌肉如心肌、骨骼肌或平滑肌、胃肠道囊状细胞、甲状腺滤泡细胞、肾上腺皮质、肝脏、松果体、骨、基质细胞、肾小管、膀胱和多种皮质及皮质下区,包括脊髓运动神经元。
除非另有说明,否则可将对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性的本发明SARM设想在本发明的所有实施方案中还对正常前列腺组织具有激动剂、拮抗剂或无活性。
本发明所用术语“无活性或激动剂活性”优选指与对照组动物相比,在体内对腹前列腺、精囊、肛提肌的重量和/或黄体生成素血清水平具有激活作用(大于5%)的化合物,最优选具有保持ugonadal温血雄性哺乳动物(优选人类男性)的平均正常骨密度、平均正常肌肉量、平均正常繁殖功能和/或平均正常性欲的活性的化合物。在对激素依赖性肿瘤呈现拮抗活性的相同剂量或剂量范围时,优选本发明SARM“无活性或激动剂活性”。当给予患者服用时,其中该SARM对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性的该剂量或剂量范围,是优选的治疗有效范围。本领域技术人员在阅读本公开内容时将清楚,当使用优选治疗有效范围以外的剂量时,本发明的SARM可能对激素依赖性肿瘤呈现相同的拮抗活性,并对不含肿瘤的组织无活性或呈现激动活性,或者可能不再呈现相同的特异性或选择性。例如,当使用该优选治疗有效范围以外的剂量时,本发明的SARM对不含肿瘤的组织呈现出某些拮抗活性。
本发明涉及具有这些双重活性的SARM、鉴定这些SARM的方法、包含这些SARM的药用组合物以及应用这些SARM治疗由雄性激素受体介导的疾病和病症的方法。
例如,本发明的SARM可用于选择性抑制激素依赖性肿瘤的生长,同时优选激活其它含雄激素受体的非肿瘤(意指无癌或无恶性肿瘤)组织的雄性激素受体活性。因此,本发明的SARM可用于治疗肿瘤,包括但不限于含雄激素受体的肿瘤,如前列腺、乳腺、大脑、皮肤、卵巢、膀胱、淋巴、肝和肾癌以及胰癌,同时缓解或消除不需要的副作用,这些副作用与在其它含雄激素受体的非肿瘤组织中抑制雄激素受体活性有关。由在治疗前列腺癌症中,用目前抗雄性激素疗法拮抗雄激素(如二氢睾丸素)正常功能而引起的某些潜在的不需要的副作用包括但不限于肌肉消瘦/恶质病、失去性欲、骨质疏松症和男子女性型乳房。
这些SARM的另一优选用途为化学预防领域,尤其适合于前列腺癌。可在放射性前列腺切除后的“观察期”,给予本发明的SARM以降低转移前列腺癌的复发率。
另外,这些SARM用于治疗雄激素依赖性的与年龄有关的疾病及病症,包括但不限于恶质病和骨质疏松症。这些药物提供一种口服生物利用性的雄激素替代疗法,但并不增加用传统雄激素激动剂治疗可见的前列腺癌风险。
预期本发明的SARM还可用于通过给予雄激素受体调节剂可治疗的其它病症,如女性多毛症、痤疮、皮脂溢、阿尔茨海默氏病、雄激素性脱发、性腺机能减退、多毛症、良性前列腺肥大、调节VEGF表达及其用作抗血管发生剂的各种应用、抑制精子生成、性欲、子宫内膜异位症、多囊卵巢综合症、厌食症、雄激素依赖性的年龄相关性疾病和病症,例如男性年龄相关性睾丸素水平降低的雄激素补充、雄性绝经、雄性激素替代、雄性或雌性性功能障碍以及抑制非卧床患者的肌肉萎缩。
可使用多种方法鉴别对激素依赖性肿瘤呈现拮抗活性,同时对含雄激素受体的其它非肿瘤组织无活性或更优选呈现激动活性的SARM。在一个实施方案中,通过筛选体外或体内对激素依赖性肿瘤细胞系的生长抑制作用,确定对激素依赖性肿瘤细胞的拮抗活性。用于筛选潜在SARM的激素依赖性肿瘤细胞系的实例包括但不限于人乳腺肿瘤细胞系MDA MB453、人乳腺肿瘤细胞系ZR-75-1、小鼠乳腺细胞系Shionogi、大鼠前列腺腺癌细胞系Dunning R-3327、人前列腺肿瘤细胞系MDA PCa 2b和PCa 2b、人前列腺细胞系LNCap、人前列腺肿瘤细胞系CWR22、人前列腺肿瘤细胞系LuCap35和LuCap23.12、人前列腺细胞系LAPC-4和LAPC-9、人前列腺肿瘤细胞系PC-295、人前列腺肿瘤细胞系PC-310和人骨肉瘤细胞系MG-63。这些测定性的人和小鼠前列腺和乳腺细胞系以及源于其的肿瘤模型系统是本领域技术人员公知的,其用于说明人体激素依赖性肿瘤(例如前列腺癌)药理学。这些模型与人体疾病的相互关系的实例可在下列(但不限于)参考文献及其其中包含的参考文献中发现:Jacques等,Endocrinology 140,416-421(1991);Yeap等,Endocrinology 140,3282-3291(1999),Sharma等,Oncogege 18,5349-5355(1999),Isaacs,J.T.Urol.Oncol.2,115-116(1996),Bentei等,In Vitro Cell Dev.Biol.35,655-662(1999),Suzuki等,J.Steroid Biochem.Mol.Biol.37,559-567(1990),Peehl,D.M.Urol.Oncol.2,100-102(1996),Wytske等,Urol.Oncol.2,122-125(1996),Leland,C.W.K.Urol.Oncol.2,126-128(1996),Buhler等,The Prostate 43,63-70(2000),Navone等,Clin.Cancer Res.,6,1190-1197(2000),Etreby等,The Prostate 42,99-106(2000),Jongsma等,Cancer Res.,60,741-748(2000),Jongsma等,Amer.J.Path.,154,543-551(1999),Ye等,Clin.Cancer Res.,5,2171-2177(1999),Navone等,Clin.Cancer Res.,3,2493-2500(1997),Klein等,Nature Medicine 3,402-408(1997),Chen等,Cancer Res,58,2777-2783(1998)和Craft等,Cancer Res.,59,5030-5036(1999)。
在该实施方案中,也可用正常的、非肿瘤细胞系测定潜在SARM的激动或拮抗活性。可用于该方法的正常非肿瘤细胞系包括但不限于原代大鼠前列腺上皮和基质细胞、小鼠肌肉细胞系C2C12、原代豚鼠平滑肌细胞、源于未成熟(I-PSMC)或成年(A-PSMC)大鼠阴茎的原代平滑肌细胞、原代兔平滑肌细胞系、前列腺平滑肌细胞系PS-1、前列腺平滑肌细胞系PSMCl、小鼠骨细胞培养物和成骨细胞系以及原代大鼠精囊系SVC-1和SCV-2。这些细胞系在下列示例性参考文献及其中包含的参考文献中有介绍:Nemeth等,J.Andrology 19,718-724(1998),Zhuang等,J.Steroid Biochem.Mol.Biol.41,693-696(1992),Zhang等,Prostate 30,117-129(1997),Ricciardelli等,J.Endocrinol.140,373-383(1994),Gonzalez-Cadavid等,Mol.Cell.Endocrinol.90,219-229(1993),Sadeghi-Nejad等,Int.J.Impotence Res.10,165-169(1998),Gerdes等,Endocrinology 139,3569-3577(1998),Sarah等,J.Cell.Physiol.185,416-424(2000),Chen等,FEBS Letters491,91-93(2001)和Tajana等,EMBO J.3,637-644(1984)。
另外,SARM的激动或拮抗作用可通过一系列体内大鼠模型用非肿瘤组织测定,其中通过测定血浆黄体生成素(LH)的水平,测定包括但不限于前列腺、精囊、肛提肌以及下丘脑轴的组织中的替代物终点。还可利用一些体内替代物的终点测定测定药物对AR途径的影响。这些测定包括测定测定药物对正常雄激素依赖性组织和功能的作用,这些正常组织和功能包括但不限于前列腺、精囊、肛提肌、骨、性欲、生育力和下丘脑(测定血液LH水平)。这些测定由于与药物对人体AR途径作用直接相关而得到广泛认可。这样的体内替代物终点测定的某些实例可在下列(但不限于)参考文献及其中包含的参考文献中发现:Ashby等,J.Appl.Tox.20,35-47(2000),Yamada等,Tox.Sciences 53,289-296(2000),Hamann等,J.Med.Chem.41,623-639(1998),Furr等.Eur.Urol 29,83-95(1996),Broulik等,Bone 20,473-475(1997),Wang等,Poster #P3-126,Endocrine Society 80th AnnualMeeting(1998),Hamann等,Presentation #S39-2,Endocrine Society 80thAnnual Meeting(1998),Maucher等,J.Cancer Res.Clin.Oncol.119,669-674(1993)和Risek等,Presentation #P1-497,Endocrine Society 83thAnnual Meeting(2001)。
还可用带有激素依赖性肿瘤的动物模型确定潜在的SARM对肿瘤的拮抗活性以及对动物包含AR的正常非肿瘤组织的激动或拮抗活性。例如,以上的体内替代物终点测定可采用带有雄激素依赖性大鼠前列腺肿瘤(如Dunning R-3327)的大鼠进行。用该方法可测定SARM对大鼠雄激素依赖性前列腺肿瘤的作用,同时通过测定血浆的LH水平,测定该SARM剂对包含AR的正常非肿瘤组织(包括但不限于前列腺、精囊、肛提肌)作用以及对下丘脑轴的作用。可以以类似的方式,使用带有人雄激素依赖性前列腺肿瘤的无免疫的裸大鼠。用该方法可测定SARM对人雄激素依赖性前列腺肿瘤的作用,同时通过测定血浆的LH水平,测定该SARM剂对正常组织(包括但不限于前列腺、精囊、肛提肌)作用以及对下丘脑轴的作用。另外,可用体内大鼠测定测定SARM对性欲和繁殖的作用。
对激素诱发的肿瘤呈现拮抗活性,而对其它非肿瘤组织无活性或更优选呈现激动活性的SARM,也可通过利用AR晶体结构和雌二醇、他莫昔芬或雷洛昔芬的雌激素受体(ER)晶体结构的信息设计。已测定雄激素受体配体结合结构域(AR-LBD)晶体结构为2.0埃的分辨度,并在结合到本发明中作为参考的2000年10月13日申请的美国专利申请序列号09/687,609以及相应的PCT/US00/28495,Matias等,J.Biol.Chem.275,26164-16171(2000)以及Sack等,Proc.Natl.Acad.Sci.USA 98,4904-4909(2001)中说明。例如WO 99/50658(通过引用结合到本文中)公开了ER的晶体结构。可用这些晶体结构、结构型或合理药物设计技术设计、选择和合成化学实体,包括本发明的抑制和刺激性SARM。
本发明可用的一具体有用的药物设计技术是迭代药物设计。迭代药物设计是一种通过测定或评估蛋白质/配体复合物的连续套三维结构,优化蛋白质和化合物之间结合的方法。本领域技术人员将清楚在本公开内容中,天然配体或底物与其对应的受体或酶的结合空穴(binding pocket)的结合是多种生理作用机制的基础。本文所用术语“结合空穴”指分子或分子复合物的区域,因为其形状有利于与另一化学实体或化合物(即配体)结合。类似地,许多药物通过与受体和酶的结合部位结合发挥其生理作用。这种结合可发生在所有或任何部分的结合部位。理解这种结合有助于设计更易于与其靶受体或酶结合的性质的药物,从而提高了生理效能。因此,该信息在设计本发明潜在SARM中非常有用。
术语“与…结合”指化学实体或化合物或其部分(即配体)之间的接近状态。这种结合可以是非共价键的,其中该接近能量上受氢键或范德华力或静电相互作用支持,或者可以是共价键结合。
迭代药物设计时,先获得一系列蛋白质/配体复合物的晶体。然后将各复合物的三维结构解析。这一途径提供各复合物蛋白质和配体之间的结合的深入了解。如下达到该目的:选择具有抑制活性的化合物、获得该新蛋白质/配体复合物的晶体、解析该复合物的三维结构以及比较新蛋白质/配体复合物之间的结合和先前解析的蛋白质/配体复合物之间的结合。通过观察化合物变化如何实现蛋白质/配体结合,可优化结合。
在某些情况下,通过形成连续的蛋白质/配体复合物,然后结晶各个新复合物,进行迭代药物设计。另外,在存在抑制剂的情况下浸入预形成的蛋白质晶体,形成蛋白质/配体复合物,而不需要结晶各个蛋白质/配体复合物。
本文所用术语“浸入(soaked)”指该晶体转移至包含所研究的化合物的溶液中的过程。
本发明还提供利用雄激素和/或雌激素的三维模型计算机方法,该方法基于AR-LBD/AR-LBD配体复合物和/或ER-LBD/ER-LBD配体复合物的晶体。一般地,设计受体配体的计算机方法先确定与该配体的至少一个化学部分相互作用的受体配体结合结构域的氨基酸。然后采用包含AR-LBD或ER-LBD的晶体化蛋白质的三维模型,将该配体接合到该受体LBD的结合部位中。然后优化该配体结合部位的取向(见后),之后用其设计至少一个配体化学部分的化学修饰体,该修饰体产生该配体结构的第二个化学部分,与互作氨基酸同天然激素中对应的化学部分之间的相互作用相比,它降低或增加受体LBD中的互作氨基酸与第二个化学部分之间的相互作用。
本发明的计算机方法通过利用这些晶体和三维结构信息产生能调节雄激素受体LBD和/或雌激素受体LBD的构象变化的合成配体,从而设计SARM。这些计算机方法尤其用于设计雄激素受体的SARM,其中SARM具有延伸的部分,其能抑制任何一种配体诱发的分子作用,该作用可改变受体对基因表达的调节的影响,如抑制在天然存在的配体或其它模拟天然存在配体的配体(如激动剂)观测到的激活结构域的正常配位。基于与激动剂或拮抗剂复合的ER-LBD的结构(Shiau等,Cell 1998 95:927-937;Pike等,EMBO J.199918(17):4608-4618)以及与DHT或其它配体偶合的AR-LBD的结构(见全部结合到本发明中作为参考的2000年10月13日申请的美国专利申请序列号09/687,609和对应的PCT/US00/28495以及本发明提供的表A),可确定如何修饰化学化合物,以使它们特异性地与结合部位中的AR-LBD氨基酸相互作用。更详细地讲,可以以一种方式将上述延伸部分针对AR-结构的螺旋-12部分,从而影响在与他莫昔芬或雷洛昔芬复合的ER的结构所见的该螺旋的位置,它不同于与DHT或R1881(为更强作用激动剂的DHT合成类似物)(Matias等,J.Biol.Chem.275,26164-16171(2000))结合的AR晶体结构以及与雌二醇结合的ER晶体结构所见的螺旋-12的位置。可能影响或接触配体AR-LBD结合部位的螺旋-12上的残基包括M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906和L907。本发明还涉及表A所列的结构配位定义的三维晶体结构。本发明的晶体结构优选包含至少25%,更优选至少50%,更优选至少75%,更优选至少90%,更优选至少95%,更优选至少99%,以及最优选100%表A所列的配位。更优选提供分子或分子复合物,其包含本发明提供的表A中AR-LBD氨基酸V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907的结构配位定义的所有或任何部分的配体结合结构域,或者所述分子或分子复合物的突变体或同系物。最优选包含表A AR-LBD氨基酸N705、W741、Q711、R752、F764、T877、M895和I898的结构配位定义的所有或任何部分的配体结合结构域的分子或分子复合物,或者所述分子或分子复合物的突变体或同系物。
本文所用术语“复合物”或“分子复合物”是指以共价键或非共价键与化学实体或配体结合的AR-LBD或AR-LBD的突变体或同系物。
本发明所用的“至少一部分”指由上述结构配位定义的整个或任何部分的配体结合位点。
本文所用术语“突变体或同系物”是指具有AR-LBD类似结构和/或序列的分子或分子复合物。“类似结构”是指具有结合空穴的突变体或同系物,该空穴与所述AR-LBD氨基酸的主链原子的均方根偏差在1.5埃以下。“类似序列”是指与AR-LBD具有30%或更优选75%同一性的突变体或同系物。
“均方根偏差”指均数偏差平方的算术平均值的平方根。它是一种表达与趋势或目标的偏差或变化的方法。本发明的“均方根偏差”的定义为:根据本发明所述结构配位定义,蛋白质或蛋白质复合物的主链与所述复合物的AR部分的主链相关部分之间的变化。
一经确定蛋白质结晶的结构配位,即可用于解析其它晶体的结构。
因此,本发明可将雄激素受体/配体复合物的结构配位或其部分储存在机器可读数据储存介质。可将这些数据用于各种目的,如发现药物以及X-射线晶型分析或蛋白质晶体。
因此,本发明的一个实施方案提供一种机器可读数据储存介质,其包含表A中给出的结构配位编码的数据贮存材料。一个实施方案利用WO 98/11134中公开的System 10,所述文献公开内容结合到本发明中作为参考。
表A中给出的结构配位还可用于帮助获得其它晶体分子或分子复合物的结构信息。这可通过任何熟知的技术(包括分子替换)实现。
表A中给出的结构配位还可用于确定至少一部分的分子或分子复合物的三维结构,所述分子或分子复合物至少与AR具有某些结构上的类似特征。更详细地讲,可得到其它晶体分子或分子复合物的结构信息。这可通过任何熟知的技术(包括分子替换)实现。
因此,本发明的另一个实施方案提供利用分子替换法获得结构未知的晶体分子或分子复合物的结构信息,其包含下列步骤:a)做出该晶体分子或分子复合物的X-射线衍射图;b)将至少一部分表A中给出的结构配位运用于该X-射线衍射图中,制成该结构未知的分子或分子复合物的三维电子密度图;和c)用表A中给出的全部或部分结构配位制成AR-LBD或者任何其它核激素受体配体结合结构域的同源模型。
优选通过将本发明的晶体浸入溶液中形成晶体化分子或分子复合物。
通过采用分子替换法,可比从头开始确定这些信息更快速、更有效地得到本发明的AR-LBD/AR-LBD配体复合物或者未知结构的分子复合物的所有或部分结构配位。
分子替换法为未知结构提供了准确的相位判断。相位是一种用于解析不能直接测定的晶体结构的方程因子。通过分子替换法以外方法获得准确的相位值是一种非常耗时的过程,其需要逐次接近法和结构改进法的反复循环,并严重干扰晶体结构溶液。但是,当已解析含有至少一部分同源结构的蛋白质的晶体结构时,该已知结构的相位即可为未知结构提供满意的相位推测。
因此,该方法涉及将结构配位未知的分子或分子复合物创造出初步的模型,其通过将表A中的AR-LBD/AR-LBD配体复合物的相关的部分在该未知的分子或分子复合物的单位晶胞内定向和定位,这样可更好地说明结构未知的分子或分子复合物的所测的晶体X-射线衍射图谱。然后根据该模型计算相位,并将该相位与所测的X-射线衍射图谱振幅结合,产生配位未知的结构的电子密度图。可再将其用于任何熟知的模型建立和结构改进技术,提供未知晶体分子或分子复合物的最终的准确结构[E.Lattman,“Use of the Rotation andTranslation Functions”Meth.Enzymol.,115,pp.55-77(1985);M.G.Rossmann等,“The Molecular Replacement Method”,Int.Sci.Rev.Set.,No.13,Gordon & Breach,New York(1972)]。
可通过该方法解析与AR-LBD/AR-LBD配体或配体复合物的任何部分具有足够同源性的任何晶体分子或分子复合物、或其突变体、同系物或孤独受体的任何部分的结构。除以上提到的AR之外,还存在多种受体,其激活或失活配体没有表征获得。可将这些蛋白质归类为核激素受体,原因是其与AR具有密切同源性,这些蛋白质称为孤独受体。
还可将该结构配位特别用于解析与多种化学实体共复合的结晶AR-LBD/AR-LBD配体的结构。该方法能够确定化学实体之间相互作用的最适位置,包括候选AR抑制剂与所述复合物的相互作用。例如,从暴露于不同类型溶剂的晶体收集得到高分辨X-射线衍射数据,可确定各类型溶剂分子的保留位置。然后对与这些位置紧密结合的小分子进行设计、合成并测试其AR抑制活性。
可采用熟知的X-射线衍射技术研究以上提到的所有复合物,并可应用计算机软件,如X-PLOR[耶鲁大学,1992,MolecularSimulations,Inc.销售,参见例如Blundell & Johnson,同上;Meth.Enzymol.,vol.114 & 115,H.W.Wyckoff等主编,AcademicPress(1995)],使1.5-3埃分辨率的X-射线数据精确至约不大于0.02的R值。因此,可利用该信息优化已知的AR激动剂、部分激动剂、拮抗剂、部分拮抗剂和SARM,更重要的是设计新的AR激动剂/拮抗剂。
因此,本发明还涉及AR-LBD配体的AR-LBD结合部位,其中AR-LBD配体以范德华力或氢键与表A中AR-LBD的以下残基中的至少一个接触:V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907。本发明AR-LBD的结合部位还包括其突变体或同系物。在一个优选方案中,该突变体或同系物与表A中的AR-LBD结合部位的残基V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907具有至少25%的同一性,更优选50%同一性,更优选75%同一性,最优选95%同一性。
本发明还涉及一种机器可读数据贮存介质,其包括机器可读数据编码的数据贮存材料,其中所述数据由表A中AR-LBD/AR-LBD配体或复合物的同系物结构配位定义,其中所述同系物包含与所述复合物主链原子的均方根偏差不超过3.0埃的主链原子。本发明的机器可读数据贮存介质,优选其中所述分子或分子复合物由表A中AR-LBD/AR-LBD配体或所述分子或分子复合物的同系物的结构配位组定义,其中所述同系物与所述氨基酸的主链原子的均方根偏差不超过2.0埃。在一个优选实施方案中,所述机器可读数据贮存介质包含第一套机器可读数据编码的数据贮存材料,其包含傅立叶转换的表A中的AR-LBD/AR-LBD配体的至少一部分结构配位;当结合包含未知结构的分子或分子复合物的X-射线衍射图谱的第二套机器可读数据时,其可利用所述第一套和第二套数据按照说明书编程的机器,确定对应于第二套机器可读数据的至少一部分结构配位;所述第一套数据和第二套数据。
本发明还提供利用雄激素的三维模型的计算机方法,该方法基于AR-LBD/AR-LBD配体复合物的晶体。一般地,设计雄激素受体配体的计算机方法先确定与配体的化学部分(至少一个)相互作用的AR-LBD的氨基酸,其采用包含AR-LBD和结合的配体的晶体化蛋白质的三维模型,然后选择化学部分的化学修饰物(至少一种)制备具有一定结构的第二化学部分,与互作氨基酸同天然激素对应化学部分之间的相互作用相比,该结构降低或增加互作氨基酸与第二化学部分之间的相互作用。在一个优选实施方案中,鉴别调节雄激素受体活性的化合物的方法包括下列步骤的任意组合:
a.建立空间上适合于表A的结构配位定义的AR-LBD的试验化合物模型,或者利用AR-LBD、突变AR-LBD或AR-LBD同系物或其部分的三维结构模型;
b.利用本发明给出的AR-LBD结构配位或配体结合位点,鉴定结构和化学特征;
c.利用所确定的结构和化学特征,设计或选择潜在SARM的化合物;
d.利用所述三维结构模型或配体结合位点,设计或选择潜在SARM化合物;
e.合成潜在的SARM;
f.用特征为试验化合物结合所述AR-LBD的测定筛选潜在的SARM;
g.修饰或置换AR-LBD中的一个或多个氨基酸,AR-LBD选自表A的AR-LBD:V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907。
本发明的计算机方法通过利用所述晶体和三维结构信息产生能调节雄激素受体LBD的构象变化的合成配体,从而设计雄激素受体合成配体。这些计算机方法尤其用于设计雄激素受体的激动剂、部分激动剂、拮抗剂或部分拮抗剂或SARM上,其中所述激动剂、部分激动剂、拮抗剂或部分拮抗剂或SARM具有延伸部分,其能抑制任何一种配体诱发的分子作用,该作用可改变受体对基因表达的调节的影响,如抑制在天然存在的配体或其它模拟天然存在配体的配体(如激动剂)中观测到的活化结构域的正常配位。如上所述,雄激素受体的合成配体可用于调节雄激素受体在各种病症中的活性。
还可设计一种以稳定或破坏关键配体-受体相互作用的螺旋-3或螺旋-11为目标的延伸化学部分(Humm等,Arch.Pharm.(Weinhein)1990 323:83-87;Poujol等,J.Biol.Chem.2000 275(31):24022-24031)。与DHT复合的AR-LBD的结构表明该雄激素(DHT)的17α-羟基与AR-LBD的Thr-877和Asn-705形成关键的氢键(Sack等,Proc.Natl Acad.Sci.(USA)98(9):4904-4909(2001))。测定表明当Asn-705突变成丙氨酸(N705A)时,与野生型AR相比,该非甾体抗雄性激素具有较低的拮抗性质。因此,Asn-705在非甾体抗雄性激素的固定以及设计针对Asn-705的化学部分中起着关键作用,也可将Thr-877用于研制SARM。如上所述,雄激素受体的合成配体可用于抑制雄激素受体在激素诱发的肿瘤中的活性,而在其它含雄激素受体的非肿瘤组织中具有激活雄激素受体的活性。
以下说明ER-LBD和AR-LBD的三维结构的二级结构(SS)元素的定位。氨基酸序列对比基于AR-LBD和ER-LBD的结构叠加。序列编号为AR-LBD的编号。H(或G)表示特定的氨基酸处于螺旋中,E(或B)表示特定的氨基酸处于β链。AR-LBD氨基酸从Ile-672延伸至His-917(SEQ ID NO:1),ER-LBD氨基酸从Ser-305延伸至Arg-548(SEQ ID NO:2)。在下列序列和结构定义中标示螺旋的编号。
现有多种可利用晶体学数据(如AR和ER提供的数据)的计算机程序,这些程序能够对本发明SARM进行合理设计。可用AR和ER晶体的原子配位,利用软件程序如ICM(2.7或更高版本;Molsoft LLC,La Jolla,CA)或SYBYL_(Tripos Inc.St Louis,MO)制出配体结合的三维模型和/或确定该结构。其它分子显现程序,如INSIGHT II_(Pharmacopeia/Molecular Simulations,Inc.,San Diego,CA)和GRASP(Columbia University,New York,NY)可供进一步设计之用,并能引进新的结构。另外,现有多种可编入AR-LBD序列和AR-LBD结构的计算机模型系统。计算机系统随后产生潜在AR调节剂结合的位置的结构细节,由此可确定该潜在调节剂的互补结构细节。这些模型系统中的设计一般以能与AR-LBD物理上或结构上结合的化合物为基础。另外,该化合物必须能够呈现可与AR-LBD结合的构象。某些模型系统可在准确合成及测定之前,推测潜在AR调节剂的潜在抑制作用或结合作用。
筛选化学实体或片段结合AR和ER的能力的方法也是熟知的。这些方法一般从计算机筛选活性部位的直观研究开始。然后将所选的片段或化学实体与AR-LBD或ER-LBD定位。应用软件进行对接,然后通过全局优化方法或分子动力学和最小化方案,采用标准分子机械力场如CHARM和AMBER,优化配体受体结合位点。帮助分子对接和选择本发明所用的化学片段或化学实体的计算机程序的实例包括但不限于GRID(Doodford,P.J.J.Med.Chem,1985 28:849-857)、AUTODOCK(Goodsell,D.S.和Olsen,A.J.Proteins,Structure,Function,and Genetics 1990 8:195-202)和DOCK(Kunts等,J.Mol.Biol.1982 161:269-288)和ICM(Molsoft LLC,La Jolla,CA,ICM 2.7程序手册,Abagan等,1994,J.Med.Biol.235:983-1002,Totrov等,1997Proteins Suppl.1:215-220)。
在选择优选的化学实体或片段时,可将彼此与AR或ER的关系形像化,可将该化学实体或片段组合成单一的潜在调节剂。组合该单一化学实体中所用的程序包括但不限于CAVEAT(Bartlett等,Molecular Recognition in Chemical and Biological Problem SpecialPublication,Royal Chem.Soc.78,182-196(1989))和3D数据库系统(Martin,Y.C.J.Med.Chem,1992 35:2145-2154)。
另外,可采用空活性部位或者任选包含已知抑制剂的某些部位,从头开始设计化合物。这种类型的设计包括但不限于LUDI(Bohm H-J,J.Comp.Aid.Molec.Design 1992:6:61-78)和LeapFrogTM(TriposAssociates,St.Louis.MO)。
已研制出多种方案评价所设计和对接的化学实体受体结合部位中的。评价化学实体蛋白质结合部位所用的程序包括但不限于DOCK(Kunts等,J.Mol.Biol.1982 161:269-288)、ICM(Molsoft LLC,La Jolla,CA,Totrov等,1997 Proteins Suppl.1:215-220,Schapira等,2000 Proc.Natl.Acad.Sci USA 97(3):1008-1013)和SYBYL_(Tripos Inc.St Louis.MO)。
一经合成计算机设计的配体(CDL),即可用本发明所述的那些测定测试,以证实其作为拮抗剂对激素依赖性肿瘤的活性,并评价其对其它含AR的非肿瘤组织的活性。CDL在激素依赖性肿瘤中作为拮抗剂,并在其它含AR的非肿瘤组织中无活性或更优选呈现部分激动活性或者激动剂活性,是本发明的一种SARM。测试后,可通过结合LBD的CDL,制出LBD晶体,而将CDL进一步改善。然后将该CDL结构进一步改善,其采用已确立的三维模型的化学修饰方法改进CDL的活性或亲和性,然后制出具有改进性质的第二代CDL,如“超级SARM”,是指具有较高激动活性同时保持在所选组织中的拮抗作用的化合物。
本发明的特别优选实施方案中,设计了具有下列活性水平的化合物。在本发明的方法和组合物中,优选这些SARM,其呈现下列部分(i)和/或(ii)中所述的拮抗活性水平,以及下列部分(iii)和/或(iv)中所述的无活性或更优选的激动活性水平:
(i)对于抑制至少一种激素依赖性肿瘤细胞系,优选前列腺肿瘤细胞系或预示前列腺肿瘤细胞系活性的其它种激素依赖性肿瘤细胞系,如与筛选本发明SARM相关的以及以下实施例3、4和6中说明的那些细胞系,相对于DHT得到的最大信号诱导,IC50值不大于约1μM,更优选不大于0.5μM,最优选不大于0.1μM;和/或
(ii)在以上所述模型及以下实施例10、11、12或13中,对体内激素依赖性肿瘤生长具有抑制作用;并优选
(iii)在正常AR-敏感组织中,与DHT相比,在1μM下,至少有30%激活作用,更优选EC50值不大于约0.5μM,最优选EC50值不大于约0.1μM;和/或
(iv)如以上及实施例8中所述,与对照组动物相比,在对腹前列腺、精囊、肛提肌的重量和/或黄体生成素血清水平上,体内激活作用大于20%,优选大于40%,更优选大于70%,更优选大于90%。本发明优选的SARM也可用于保持ugonadal温血雄性哺乳动物(优选人类男性)的平均正常骨密度、平均正常肌肉量、平均正常繁殖功能和平均正常性欲。在优选实施方案中,本发明的SARM对激素依赖性肿瘤呈现拮抗活性,同时在相同剂量或剂量范围时,对正常组织无活性或呈现激动活性。当给予患者服用时,该剂量或剂量范围是优选的治疗有效范围。本领域技术人员在阅读本公开内容时将清楚,当使用该优选治疗有效范围以外的剂量时,本发明的SARM可能对激素依赖性肿瘤呈现相同的拮抗活性,并对不含肿瘤的组织无活性或呈现激动活性,或者可能不再呈现相同的特异性或选择性。例如,当使用该优选治疗有效范围以外的剂量时,本发明的SARM对不含肿瘤的组织呈现出某些拮抗活性。
本发明还涉及选择性雄激素受体调节剂(SARM),其包括对激素诱发的肿瘤具有拮抗作用而对AR的其它非肿瘤组织无活性或优选具有激动活性的任何化合物。在优选实施方案中,SARM可通过本发明所给出的筛选测定鉴别,或者根据本文所述的计算机方法设计。优选小分子化合物,尤其是不是肽或甾体类的化合物。虽然并不限定具体的化学类型,但优选选自下式Ia或Ib的化合物作为本发明的SARM,尤其是本发明实施例给出的这些结构式的具体化合物。式Ia化合物详见(作为“式I”化合物)2000年6月28日申请的美国临时专利申请序列号60/214,392、2001年4月18日申请的美国临时专利申请序列号60/284,617和Salvati等在2001年6月20日申请(代理登记号LD0191(NP))的题为“核激素受体功能的稠合环调节剂”;式Ib化合物详见(作为“式I”化合物)2000年9月19日申请的美国临时专利申请序列号60/233,519、2001年4月18日申请的美国临时专利申请序列号60/284,730和Salvati等在2001年6月20日申请(代理登记号LD0192(NP))的题为“稠合杂环琥珀酰亚胺化合物及其类似物,核激素受体功能的调节剂”;所有这些申请均整体结合到本发明中作为参考。式Ia如下:其中除非另有说明,否则各符号具有以下意义,并且各自独立选自:
G是芳基或杂环基(如杂芳基),其中该基团是单-或多环,并且在一个或多个位置上被任选取代,优选被以下基团取代:氢、烷基或取代的烷基、链烯基或取代的链烯基、炔基或取代的炔基、卤代、环烷基或取代的环烷基、环链烯基或取代的环链烯基、芳基或取代的芳基、杂环基或取代的杂环基、芳烷基或取代的芳烷基、杂环烷基或取代的杂环烷基、CN、R1OC=O、R1C=O、R1C=S、R1HNC=O、R1R2NC=O、HOCR3R3’、硝基、R1OCH2、R1O、NH2、NR4R5、SR1、S=OR1、SO2R1、SO2OR1、SO2NR1R1’、(R1O)(R1’O)P=O、(R1)(R1’)P=O或(R1’)(NHR1)P=O;
E是C=Z2、CR7R7’(如CHR7)、SO2、P=OR2或P=OOR2;
Z1是O、S、NH或NR6;
Z2是O、S、NH或NR6;
A1是CR7或N;
A2是CR7或N;
Y是J-J’-J”,其中J是(CR7R7’)n,n=0-3,J’是键或O、S、S=O、SO2、NH、NR6、C=O、OC=O、NR1C=O、CR7R7’、C=CR8R8’、R2P=O、OPOOR2、OPO2、OSO2、C=N、NHNH、NHNR6、NR6NH、N=N、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环烷基或者芳基或取代的芳基,J”是(CR7R7’)n,n=O-
3,其中Y不是键;
W是CR7R7’-CR7R7’、CR8=CR8’、CR7R7’-C=O、NR9-CR7R7’、N=CR8、N=N、NR9-NR9’、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环烷基或者芳基或取代的芳基;
Q是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环烷基或取代的杂环烷基、芳基烷基或取代的芳基烷基、炔基或取代的炔基、芳基或取代的芳基、杂环基(如杂芳基)或取代的杂环基(如取代的杂芳基)、卤代、CN、R1OC=O、R4C=O、R5R6NC=O、HOCR7R7’、硝基、R1OCH2、R1O、NH2、C=OSR1、SO2R1或NR4R5;
M是键、O、CR7R7’或NR10,M’是键或NR10,条件是M或M’至少一个必须是键;
L是键、(CR7R7’)n、NH、NR5或N(CR7R7’)n,其中n=0-3;
R1和R1’各自独立是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基;
R2是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基;
R3和R3’各自独立是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、卤代、CN、羟胺、羟基酰胺、烷氧基或取代的烷氧基、氨基、NR1R2、硫醇基、烷硫基或取代的烷硫基;
R4是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、R1C=O、R1NHC=O、SO2OR1或SO2NR1R1’;
R5是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、R1C=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’;
R6是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、CN、OH、OR1、R1C=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’;
R7和R7’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、卤代、CN、OR1、硝基、羟胺、羟基酰胺、氨基、NHR4、NR2R5、NOR1、硫醇基、烷硫基或取代的烷硫基、R1C=O、R1OC=O、R1NHC=O、SO2R1、SOR1、PO3R1R1’、R1R1’NC=O、C=OSR1、SO2R1、SO2OR1或SO2NR1R1’;
R8和R8’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、硝基、卤代、CN、OR1、氨基、NHR4、NR2R5、NOR1、烷硫基或取代的烷硫基、C=OSR1、R1OC=O、R1C=O、R1NHC=O、R1R1’NC=O、SO2OR1、S=OR1、SO2R1、PO3R1R1’或SO2NR1R1’;
R9和R9’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、CN、OH、OR1、R1C=O、R1OC=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’;和
R10是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、CN、OH、OR1、R1C=O、R1OC=O、R1R1’NC=O、SO2R1、SO2OR1或SO2NR1R1’。式Ib如下:其中除非另有说明,否则各符号具有以下意义,并且各自独立选自:
G是芳基或杂环基(如杂芳基),其中该基团是单-或多环,并且在一个或多个位置上被任选取代,优选被以下基团取代:氢、烷基或取代的烷基、链烯基或取代的链烯基、炔基或取代的炔基、卤代、环烷基或取代的环烷基、环链烯基或取代的环链烯基、芳基或取代的芳基、杂环基或取代的杂环基、芳烷基或取代的芳烷基、杂环烷基或取代的杂环烷基、CN、R1OC=O、R1C=O、R1C=S、R1HNC=O、R1R2NC=O、HOCR3R3’、硝基、R1OCH2、R1O、NH2、NR4R5、SR1、S=OR1、SO2R1、SO2OR1、SO2NR1R1’、(R1O)(R1’O)P=O、氧代、(R1)(R1’)P=O或(R1’)(NHR1)P=O;
Z1是O、S、NH或NR6;
Z2是O、S、NH或NR6;
A1是CR7或N;
A2是CR7或N;
Y是J-J’-J”,其中J是(CR7R7’)n,n=0-3,J’是键或O、S、S=O、SO2、NH、NR7、C=O、OC=O、NR1C=O、CR7H7’、C=CR8R8’、R2P=O、R2P=S、R2OP=O、R2NHP=O、OP=OOR2、OP=ONHR2、OP=OR2、OSO2、C=NR7、NHNH、NHNR6、NR6NH、N=N、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环烷基或者芳基或取代的芳基,J”是(CR7R7’)n,n=0-3,其中Y不是键;
W是CR7R7’-CR7R7’、CR8=CR8’、CR7R7’-C=O、NR9-CR7R7’、N=CR8、N=N、NR9-NR9’、S-CR7R7’、SO-CR7R7’、SO2-CR7R7’、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环烷基或者芳基或取代的芳基,其中当W不是NR9-CR7R7’、N=CR8、N=N、NR9-NR9’、S-CR7R7’、SO-CR7R7’、SO2-CR7R7’或杂环基或取代的杂环烷基时,那么J’必须是O、S、S=O、SO2、NH、NR7、OC=O、NR1C=O、OP=OOR2、OP=ONHR2、OSO2、NHNH、NHNR6、NR6NH或N=N;
Q1是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环烷基或取代的杂环烷基、芳基烷基或取代的芳基烷基、炔基或取代的炔基、芳基或取代的芳基、杂环基(如杂芳基)或取代的杂环基(如取代的杂芳基)、卤代、CN、R1OC=O、R4C=O、R5R6NC=O、HOCR7R7’、硝基、R1OCH2、R1O、NH2、C=OSR1、SO2R1或NR4R5;
Q2是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环烷基或取代的杂环烷基、芳基烷基或取代的芳基烷基、炔基或取代的炔基、芳基或取代的芳基、杂环基(如杂芳基)或取代的杂环基(如取代的杂芳基)、卤代、CN、R1OC=O、R4C=O、R5R6NC=O、HOCR7R7’、硝基、R1OCH2、R1O、NH2、C=OSR1、SO2R1或NR4R5;
L是键、(CR7R7’)n、NH、NR5、NH(CR7R7’)n或NR5(CR7R7’)n,其中n=0-3;
R1和R1’各自独立是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基;
R2是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基;
R3和R3’各自独立是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、卤代、CN、羟胺、羟基酰胺、烷氧基或取代的烷氧基、氨基、NR1R2、硫醇基、烷硫基或取代的烷硫基;
R4是H、烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、R1C=O、R1NHC=O、SO2OR1或SO2NR1R1’;
R5是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、R1C=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’;
R6是烷基或取代的烷基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、CN、OH、OR1、R1C=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’;
R7和R7’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、卤代、CN、OR1、硝基、羟胺、羟基酰胺、氨基、NHR4、NR2R5、NOR1、硫醇基、烷硫基或取代的烷硫基、R1C=O、R1OC=O、R1NHC=O、SO2R1、SOR1、PO3R1R1’、R1R1’NC=O、C=OSR1、SO2R1、SO2OR1或SO2NR1R1’,或者其中A1或A2包含R7以及W包含R7,A1或A2以及W的所述R7一起形成杂环;
R8和R8’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、硝基、卤代、CN、OR1、氨基、NHR4、NR2R5、NOR1、烷硫基或取代的烷硫基、C=OSR1、R1OC=O、R1C=O、R1NHC=O、R1R1’NC=O、SO2OR1、S=OR1、SO2R1、PO3R1R1’或SO2NR1R1’;和
R9和R9’各自独立是H、烷基或取代的烷基、链烯基或取代的链烯基、环烷基或取代的环烷基、环链烯基或取代的环链烯基、杂环基或取代的杂环基、环烷基烷基或取代的环烷基烷基、环链烯基烷基或取代的环链烯基烷基、杂环烷基或取代的杂环烷基、芳基或取代的芳基、芳基烷基或取代的芳基烷基、CN、OH、OR1、R1C=O、R1OC=O、R1NHC=O、SO2R1、SO2OR1或SO2NR1R1’。
本发明还涉及应用SARM抑制激素诱发的肿瘤的生长的方法。激素诱发的肿瘤可通过给予患者有效量的SARM治疗,其中SARM对激素诱发的肿瘤呈现拮抗作用,而对含AR的其它非肿瘤组织无活性或更优选呈现激动活性。“有效量”是指能抑制患者的激素诱发的肿瘤细胞生长的SARM的量或浓度。在优选实施方案中,“有效量”还指诱发对含AR的非肿瘤组织的激动活性的SARM的量或浓度。所述量或浓度一般可由本领域技术人员例如根据以细胞为基础的测定,如本发明所述的测定,或者通过其它本领域已知的方式确定。
可将本发明的SARM单独给服或者与放射线和/或一种或多种活性剂(如化疗剂)同时或顺序用药。与本发明化合物联合使用的抗癌剂或细胞毒性剂的类别实例包括但不限于:烷化剂,如氮芥、烷基磺酸酯、亚硝基脲、氮杂环丙烷和三氮烯类;抗代谢剂,如叶酸拮抗剂、嘌呤类似物和嘧啶类似物;抗生素类,如蒽环类、博来霉素、丝裂霉素C、更生霉素和普卡霉素;酶类,如L-天冬酰胺酶;法尼基蛋白转移酶抑制剂;5α还原酶抑制剂;17β-羟基甾体脱氢酶3型的抑制剂;激素类,如糖皮质激素、雌激素/抗雌激素、雄激素/抗雄激素、孕激素和黄体生成素-释放激素拮抗剂、醋酸奥曲肽;微管破坏剂,如海鞘素或其类似物和衍生物;微管稳定剂,如紫杉烷类,例如紫杉醇(Taxol_)、多西他赛(Taxotere_)及其类似物、epothilones类,如epothilones A-F及其类似物;植物产物,如长春花生物碱类、表鬼臼毒素、紫杉烷类;以及拓扑异构酶抑制剂;异戊烯基蛋白转移酶抑制剂;以及其它药物,如羟基脲、甲基苄肼、米托坦、六甲蜜胺、铂配位络合物,如顺铂和卡铂;以及用作抗肿瘤和细胞毒性剂的其它药物,如生物反应调节剂、生长因子;免疫调节剂和单克隆抗体。本发明化合物还可与放射疗法联合使用。
上述类别的抗癌剂或细胞毒性剂的代表性实例包括但不限于:盐酸氮芥、环磷酰胺、苯丁酸氮芥、异环磷酰胺、白消胺、卡氮芥、洛莫司汀、司莫司汀、链佐星、噻替派、达卡巴唪、甲氨蝶呤、硫鸟嘌呤、巯嘌呤、氟达拉宾、pentastatin、克拉屈滨、阿糖胞苷、氟尿嘧啶、盐酸阿霉素、正定霉素、伊达比星、硫酸博来霉素、丝裂霉素C、放线菌素D、番红菌素、番红霉素、喹癌菌素、discodermolides、长春新碱、长春花碱、酒石酸长春瑞滨、依托泊苷、磷酸依托泊苷、替尼泊苷、紫杉醇、他莫昔芬、雌氮芥、雌氮芥磷酸钠、氟他胺、布舍瑞林、亮丙瑞林、蝶啶、diyneses、左旋咪唑、aflacon、干扰素、白介素、阿地白介素、非格司亭、沙格司亭、利妥昔单抗、BCG、维A酸、盐酸依立替康、倍他米松、盐酸吉西他滨、六甲蜜胺和拓扑替康及其任何类似物或衍生物。
上述类别的优选成员包括但不限于紫杉醇、顺铂、卡铂、阿霉素、洋红霉素、正定霉素、氨基蝶呤、甲氨蝶呤、甲基叶酸、丝裂霉素C、海鞘素743或甲基丝裂霉素、5-氟尿嘧啶、6-巯基嘌呤、吉西他滨、胞嘧啶阿糖胞苷、鬼臼毒素或鬼臼毒素衍生物,如依托泊苷、磷酸依托泊苷或替尼泊苷、苯丙氨酸氮芥、长春花碱、长春新碱、异长春碱、长春地辛和环氧长春碱。
抗癌剂及其它细胞毒性剂的实例包括下列实例:德国专利号4138042.8;WO 97/19086、WO 98/22461、WO 98/25929、WO98/38192、WO 99/01124、WO 99/02224、WO 99/02514、WO 99/03848、WO 99/07692、WO 99/27890、WO 99/28324、WO 99/43653、WO99/54330、WO 99/54318、WO 99/54319、WO 99/65913、WO 99/67252、WO 99/67253和WO 00/00485中公开的epothilone衍生物;WO99/24416(另见美国专利号6,040,321)中公开的细胞周期蛋白依赖性激酶抑制剂;WO 97/30992和WO 98/54966中公开的异戊烯基蛋白转移酶抑制剂;以及美国专利号6,011,029中全面具体公开的药物(可将该美国专利的化合物与任何NHR调节剂(包括但不限于本发明的化合物),如AR调节剂、ER调节剂,以及与LHRH调节剂或与手术阉割联合应用,尤其用于肿瘤治疗)。
还可将本发明的这种组合制成制剂,或者与其它所选的治疗剂共同给药,用于与上述病症有关的给药疗法的具体应用。例如,可将本发明化合物与其它药物制成制剂,所述其它药物用于防止恶心、过敏和胃刺激性,如镇吐药物以及H1和H2抗组胺剂。
本发明的SARM,如通过本文公开的方法鉴定为SARM的化合物,当口服给予时其具有活性,可制成液体剂,例如糖浆剂、混悬剂或乳剂、片剂、胶囊剂或锭剂。液体组合物一般包含本发明化合物于适当液体载体中(如乙醇、甘油、山梨醇、非水性溶剂(如聚乙二醇)、油类或水的混悬剂或溶液剂,可含有悬浮剂、防腐剂、表面活性剂、湿润剂、矫味剂或着色剂。另外,可用再构建的粉末剂制备液体制剂。例如,将包含活性化合物、悬浮剂、蔗糖和甜味剂的粉末用水制成混悬剂;用包含活性组分、蔗糖和甜味剂的粉末制成糖浆剂。片剂形式的组合物可采用适当的药学载体如制备固体组合物的常规所用的载体制备。这些载体的实例包括硬脂酸镁、淀粉、乳糖、蔗糖、微晶纤维素和粘合剂,如聚乙烯吡咯烷酮。还可将片剂进行有色膜包衣,或者载体部分包含色素。另外,可将活性化合物制成控释剂型,如包含亲水性或疏水性基质的片剂。可采用常规包囊方法,如通过将活性化合物和赋形剂填充入硬明胶胶囊中,制成胶囊形式的组合物。其它胶囊制剂的实例包括例如活性化合物和高分子量聚乙二醇的半固体基质的填充式硬明胶胶囊剂;或者活性化合物的聚乙二醇溶液或悬浮于食用油(如液体石蜡或精馏花生油)的混悬液的填充式软明胶胶囊剂。
本发明的SARM,如通过本发明公开的方法鉴定的化合物,当非肠道给予时其具有活性,可制成如任何适于非肠道给药的适当方式(如肌内或静脉内给药)的剂型。肌内给药的典型组合物包括活性组分在油(如花生油或芝麻油)中的混悬剂或溶液剂。静脉内给药的典型组合物包括无菌等渗水溶液,其包含如活性组分、葡萄糖、氯化钠、共溶剂(如聚乙二醇)以及任选的螯合剂(如乙二胺四乙酸)和抗氧化剂(如焦亚硫酸钠)。另外,可将溶液剂冷冻干燥,然后在使用前,用适当的溶剂制成溶液剂。
本发明的SARM,如通过本发明公开的方法鉴定为SARM的化合物,当直肠给予时其具有活性,可制成栓剂。典型的栓剂一般包括活性组分及粘合剂和/或润滑剂,如明胶或可可脂或其它低熔点的植物或合成石蜡或脂肪。
本发明的SARM,如通过本发明公开的方法鉴定为SARM的化合物,当局部给予时其具有活性,可制成如经皮组合物的剂型。这种组合物包含例如衬垫式活性化合物储层、控制膜式垫片和接触粘附层。
SARM的典型日剂量可根据SARM的活性、个体的需要、所治疗的病症和给药途径而变化。典型的适合剂量为每日每kg接受者体重0.001-10mg范围。
下列非限定性实施例用于进一步说明本发明。实施例实施例1:本发明SARM实例
本发明的SARM实例在表1中说明。
下列化合物的绝对构型未经测定。为简化命名,本发明指定化合物[3aR-(3aα,4β,7β,7aα)-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈具有“R”构型,而化合物[3aS-(3aα,4β,7β,7aα)-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈本发明被指定具有“S”构型。本发明指定源于[3aR-(3aα,4β,7β,7aα)]-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈的纯对映体产物具有“R”构型,而源于[3aS-(3aα,4β,7β,7aα)]-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈的纯对映体产物本发明被指定具有“S”构型。为简化命名,本发明指定化合物[3aS-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈具有“S”构型,而化合物[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈本发明被指定具有“R”构型。本发明指定源于[3aS-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈的纯对映体产物具有“S”构型,而源于[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈的纯对映体产物本发明被指定具有“R”构型。本发明指定源于[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)-苄腈的纯对映体产物具有“R”构型,而源于[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)-苄腈的纯对映体产物本发明被指定具有“S”构型。
采用色谱技术测定表1中所述化合物的保留时间,测定条件如下:LCMS=YMC S5 ODS柱,4.6×50mm,用含有0.1%TFA的10-90%MeOH/H2O洗脱4分钟;流速4mL/min,检测波长220nm;LC=YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%MeOH/H2O洗脱4分钟;流速4mL/min,检测波长220nm。表1中所列的分子量(如果提供),通过式m/z的MS(ES)测定。表1
这些SARM实例的体外活性采用MDA MB-453乳腺肿瘤系报告性测定、Shionogi小鼠乳腺肿瘤系增殖测定以及C2C12肌细胞报告性测定测定。测定相对于DHT获得的最大信号的IC50(拮抗剂方式,在DHT存在下)和EC50(激动剂方式,在DHT不存在下)。另外,对于所述报告性测定,测定出一组药物浓度下,相对于DHT的%活化率(无DHT存在)和%抑制率(有DHT存在)。对于Shionogi增殖测定,也测定出一组药物浓度下,相对于DHT的%增殖率(无DHT存在)和%增殖抑制率(有DHT存在)。除了在上表中说明的化合物外,这些化合物都可为外消旋混合物。虽然其活性水平存在一定程度的差别,但是上表中的所有实例化合物都证实具有本发明的SARM性能。
更详细地讲,在所述MDA MB-453乳腺肿瘤系报告性测定中,所有测试的实例SARM的IC50都不大于0.8μM,EC50均大于5μM。在Shionogi小鼠乳腺肿瘤系增殖测定中,许多所测试的实例SARM观测到类似的结果。更详细地讲,某些化合物呈现不大于0.8μM的IC50值,大于5μM的EC50值。相反,在C2C12肌细胞报告性测定中,许多受试化合物呈现的IC50都不小于3μM,并且受试化合物的特别优选的亚组呈现的EC50均不大于0.8μM,或者呈现大于25%的激动活性。表1中优选的实例SARM(测试SARM)包括化合物3、7、11、13、19、23、24、25、30、31和67。
另外,可将表1 SARM的效果与成熟大鼠前列腺重量测定(MRPW,实施例9)中的完全AR拮抗剂对比。为比较AR完全拮抗剂和SARM化合物7、9和36对腹前列腺(VP)、精囊(SV)、肛提肌(LA)和黄体生成素(LH)血清水平的作用,连续14日给成熟雄性大鼠(n=5)口服用药,接着分析器官的重量和血清。与完全AR拮抗剂相比,更详细地讲,化合物2e(以下实施例2制备)和卡素地司(已知的AR拮抗剂)显示出明显的抑制作用,而SARM化合物9和36在其最高剂量(100mg/kg或“mpk”)时,仅对VP、SV和LA的重量呈现出中度抑制作用。化合物7在100mpk时,也仅呈现出适度的抑制作用,并且还呈现出(与化合物9及36相比)反向剂量反应,更加不具备作为VP、SV和LA的重量抑制剂的潜能。血清LH水平与整体对照组极为类似,如果存在任何作用的话,这些SARM对下丘脑垂体体轴的活性非常弱。
采用预防性给药方案,通过大鼠肛提肌肌肉模型(实施例8),还测定了本发明SARM化合物7和9的体内激动活性。在该动物模型中,采用性成熟(6-8周)的雄性Sprague-Dawley大鼠。将这些大鼠阉割,分成处理组,手术后3日内用测定物处理。通过对丙酸睾丸素(0.3mg/kg-3mg/kg)与这些SARM的对比的剂量-反应研究,将化合物7和9的潜在SARM作用与睾丸素比较。两种SARM的测定剂量均为90mg/kg,口服给药。与对前列腺湿重无影响的溶媒处理的阉割对照组相比,化合物7增加27%的该肛提肌湿重。化合物9对肛提肌肌肉和前列腺均无作用。
还使用裸鼠(n=8)的CWR-22前列腺癌模型,将化合物7和9(均为外消旋体)与卡素地司进行比较。将所有这三种化合物均进行连续14日的口服给药。当剂量为75mpk时,化合物7和9都呈现出与卡素地司(150mg/kg)类似的抑制作用。然后将化合物9的两种对映体分成化合物25(表1所示)及其镜像化合物25’(非表1所示)。在未成熟的前列腺湿重测定中,对这两种化合物进行体内测定。化合物25对正常组织几乎无活性,而全拮抗剂对映体化合物25’呈现明显的活性和剂量反应。化合物25呈现出出乎意料的较强的结合亲和力和拮抗活性(在MD-453中)。CWR-22人前列腺异种移植模型中的两种化合物的测定呈现出相反的活性。在19mg/kg剂量下,化合物25的作用与卡素地司(150mg/kg)相同,而化合物25’在其最大测定剂量(75mpk)下,未呈现明显的活性。
这些体内获得的数据反应了体外数据,表明这些化合物是所述两种AR依赖性肿瘤细胞系的拮抗剂,而对正常肌肉细胞系具有激动作用。实施例2:SARM的合成
本发明SARM的化学合成实例包括在以下实施例2a-2d(i)中。阅读本公开说明书的本领域技术人员清楚,除本发明给出的这些方法外,还可采用其它方法合成这些实例SARM。
本发明采用以下缩写:
DBU=1,8-二氮杂二环[5.4.0]十一烷-7-烯
4-DMAP=4-二甲氨基吡啶
ee=过量对映体
DMF=二甲基甲酰胺
EtOAc=乙酸乙酯
Me=甲基
RT=保留时间
TFA=三氟乙酸
THF=四氢呋喃
TLC=薄层色谱
pTSA=对甲苯磺酸
t-Bu=叔丁基
Ph=苯基
Pd/C=附着于活性碳上的钯
Ts=甲苯磺酰基
TBS=叔丁基二甲基硅烷
TEA=三乙胺
n-Bu=正丁基
rt=室温
LC=液相色谱
Et=乙基
MS=分子筛
MS(ES)=电子喷雾质谱
DEAD=偶氮二甲酸二乙酯
WSDCC=水溶性二羰基二亚胺1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
TBAF=四丁基氟化铵
DBAD=偶氮二甲酸二叔丁基酯
ADDP=1,1-[偶氮二羰基]二哌啶实施例2a:[5S-(5α,8α,8aα)]-2-[4-氰基-3-(三氟甲基)苯基]六氢-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-7(8H)-甲酸,1,1-二甲基乙酯(2a)的制备
向4-异氰酸基-2-(三氟甲基)-苄腈(1.0mmol)的带有4_ MS(0.300g)的甲苯(4mL)溶液中,加入(1S-外)-2,5-二氮杂双环[2.2.1]庚烷-2,6-二甲酸,2-(1,1-二甲基乙基)6-甲酯(2a(1))(0.220g,0.856mmol)的甲苯(6mL)溶液。在25℃下10小时后,加入DBU(0.166mL,1.11mmol),在81℃下,将反应物加热2小时。然后将反应物冷却至25℃,倒入1N HCl(50mL)中。然后将该溶液用二氯甲烷(3×30mL)提取,合并的有机相经无水硫酸钠干燥。得到的粗残留物经SiO2快速层析纯化,用丙酮/氯仿(0-2-4-8%丙酮)洗脱得到2a(0.155g,42%)MS(ES):m/z437.09[M+H]+。HPLC RT=3.280min(100%)(YMC S5 ODS柱,4.6×50mm;10-90%MeOH/H2O梯度,+0.1%TFA;流速4mL/min,检测波长220nm);HPLC RT=3.133min(100%)(YMC S5 ODS柱,4.6×50mm;10-90%MeOH/H2O梯度,+0.1%TFA;流速4mL/min,检测波长220nm);为白色泡沫状物。
原料化合物2a(1)制备如下:
将N-(叔丁氧基羰基)-L-4-羟基脯氨酸(10.0g,43.3mmol)溶解于THF中,冷却至0℃。然后用15分钟加入硼烷/THF(1.0M溶液,86.6mL)。然后将反应混合物温热至25℃,接着加热回流16小时。将反应瓶从加热源处移出,慢慢加入无水甲醇(35mL)。冷却至25℃后,真空除去溶剂,直接得到粗品二醇物中间体。将该粗品二醇物(1.81g,8.34mmol)溶解于二氯甲烷(50mL)中,加入2,6-二甲基吡啶(1.46mL,12.51mmol),将该混合液冷却至-78℃。然后加入二甲硅烷基三氟-甲磺酸叔丁基酯(1.92mL,8.34mmol)。2小时后,将反应混合物倒入1N HCl(100mL)中,用二氯甲烷(2×100mL)提取,有机相经无水硫酸钠干燥。得到的粗品醇经SiO2快速层析纯化,用丙酮的氯仿溶液(0-5-10%丙酮)洗脱得到1.011g(2步收率37%)的(2S-反式)-4-羟基-2-[[[(1,1-二甲基乙基)二甲硅烷基]氧基]甲基]-1-吡咯烷甲酸,1,1-二甲基乙酯(2a(2)),为澄清油状物:
将2a(2)(3.41g,10.3mmol)溶解于无水吡啶(30.0mL)中,冷却至0℃。然后用10分钟,分次加入对甲苯磺酰氯(5.89g,30.9mmol)。将该烧瓶放入4℃下的冰箱中48小时。将得到的溶液倒入1N HCl(300mL)中,用二氯甲烷(3×200mL)提取,有机相经无水硫酸钠干燥。将该粗品对甲苯磺酸酯溶解于THF(50mL)中,向其中顺次加入水(0.5mL)和pTSA-H2O(1.03mmol)。经TLC监测反应完成后,立即将该混合物倒入饱和NaHCO3水溶液(150mL)中,用二氯甲烷(3×50mL)提取。合并的有机相经硫酸钠干燥。得到的粗品醇经SiO2快速层析纯化,用丙酮/氯仿(0-5-10%丙酮)洗脱得到2.71g(2步收率71%)的(2S-反式)-2-羟基甲基-4-[[(4-甲基苯基)磺酰基]氧基]-1-吡咯烷甲酸,1,1-二甲基乙酯(2a(3)),为澄清油状物:
向-78℃草酰氯(2.0M的CH2Cl2溶液,2.82mL)的CH2Cl2(40mL)溶液中,加入无水二甲亚砜(0.462mL,6.51mmol)。将该混合液放置15分钟,然后慢慢加入2a(3)(1.61g,4.34mmol)的CH2Cl2(10mL)溶液。再经30分钟后,加入三乙胺(1.81mL,13.02mmol),将反应物慢慢温热至0℃。然后将该反应物用水(25mL)猝灭,用CH2Cl2(100mL)稀释。随后将该混合液顺次用1N HCl(1×100mL)、饱和NaHCO3水溶液(50mL)和水(2×50mL)洗涤。有机相经无水硫酸钠干燥,真空除去有机挥发物。将粗品醛中间体(1.60g,4.34mmol)溶解于THF(25mL)中,向其中顺次加入氰基磷酸二乙酯(90%,0.95mL,5.64mmol)和苄胺(1.23mL,11.3mmol)。2小时后,通过TLC监测反应完成,真空除去挥发物。残留的粗品反应混合物经SiO2快速层析纯化,用丙酮/氯仿(0-2-3%丙酮)洗脱得到1.48g(70%)的(2S-反式)-2-[氰基[(苯基甲基)氨基]甲基]-4-[[(4-甲基苯基)-磺酰基]氧基]-1-吡咯烷甲酸,1,1-二甲基乙酯(2a(4)),为白色固体。经NMR光谱检测,(2a(4))(结构如下)为约1∶1的非对映体混合物。
将2a(4)(1.48g,3.05mmol)溶解于二氯乙烷(25mL)中,加入二异丙基乙胺(1.45mL)。在密封管中,将该混合液加热至100℃下18小时。然后真空除去挥发分,得到的残留物经SiO2快速层析纯化,用丙酮/氯仿(0-2-3%丙酮)洗脱,得到(1S-内)-6-氰基-5-(苯基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸,1,1-二甲基乙酯(2a(5A))(0.51g,62%)和(1S-外)-6-氰基-5-(苯基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸,1,1-二甲基乙酯(2a(5B))(0.370g,38%)的混合物,为澄清油状物。经NOE、COESY和DEPT NMR测定后,确定这些化合物的结构:
将2a(5A)(0.400g,1.28mmol)溶解于NaOMe(0.5M,12.8mL)中,加热至60℃下5小时。将反应物冷却至0℃,慢慢加入3NHCl(4.0mL)。在0℃下2小时后,将反应物倒入饱和NaHCO3水溶液(50mL)中。将该混合液用CH2Cl2(3×50mL)提取,合并的有机相经无水硫酸钠干燥。将该粗品酯经SiO2快速层析纯化,用丙酮/氯仿(0-2-4%丙酮)洗脱,得到0.320g(0.92mmol,72%)的(1S-内)-5-(苯基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2,6-二甲酸,2-(1,1-二甲基乙基)6-甲酯(2a(6A)),为澄清油状物:
将2a(5B)(0.400g,1.28mmol)溶解于NaOMe(0.5M,12.8mL)中,加热至60℃下5小时。将反应物冷却至0℃,慢慢加入3NHCl(4.0mL)。在0℃下2小时后,将反应物倒入饱和NaHCO3水溶液(50mL)中。将该混合液用CH2Cl2(3×50mL)提取,合并的有机相经无水硫酸钠干燥。将该粗品酯经SiO2快速层析纯化,用丙酮/氯仿(0-2-4%丙酮)洗脱,得到0.290g(0.85mmol,66%)的(1S-外)-5-(苯基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2,6-二甲酸,2-(1,1-二甲基乙基)6-甲酯(2a(6B)),为澄清油状物:
将2a(6A)(0.280g,0.81mmol)溶解于无水EtOH(10.0mL)中,加入Pd/C(10%Pd,0.080g)。通过氢气球导入氢气,在25℃下,将反应物搅拌20小时。通过硅藻土过滤除去Pd,用EtOAc漂洗。真空除去挥发分得到2a(1)(0.205g,99%),为粘性黄色油状物。该化合物不经纯化直接使用。MS(ES)=m/z 257.18[M+H]+。HPLC RT=1.223min(95%)(YMC S5 ODS柱,4.6×50mm;10-90%MeOH/H2O梯度,+0.1%TFA;流速4mL/min,检测波长220nm)。实施例2b:[5S-(5α,8α,8aα)]-4-(六氢-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-2(3H)-基)-2-(三氟甲基)苄腈(2b)的制备
将2a(0.115g,0.264mmol)溶解于无水二氯甲烷(3mL)中,在25℃下,加入TFA(1.0mL)。1小时后,真空浓缩反应物,将残留物溶解于二氯甲烷中,倒入饱和NaHCO3水溶液中。然后将该溶液用CH2Cl2(3×10mL)提取,合并的有机相经无水硫酸钠干燥。得到0.089g(97%)的游离2b,为黄色固体。MS(ES):m/z 359.09[M+Na]+。HPLC RT=1.477min(100%)(YMC S5 ODS 柱,4.6×50mm;10-90%MeOH/H2O梯度,+0.1%TFA;流速4mL/min,检测波长220nm)。实施例2c:[5S-(5α,8α,8aα)]-7-(4-氟苯甲酰基)四氢-2-(4-硝基-1-萘基)-5,8-亚甲基咪唑并[1,5-a]吡嗪-1,3(2H,5H)-二酮(2c)的制备
将[5S-(5α,8α,8aα)]-四氢-2-(4-硝基-1-萘基)-5,8-亚甲基咪唑并[1,5-a]吡嗪-1,3(2H,5H)-二酮(2c(1))(0.077g,0.228mmol)溶解于二氯甲烷(2.0mL)中,加入TEA(0.127mL,0.912mmol)和4-DMAP(0.001g)。将反应物冷却至0℃,加入4-氟苯甲酰氯(0.040mL,0.342mmol)。然后将该反应物慢慢温热至25℃。3小时后,将该反应物用二氯甲烷(50mL)稀释,然后顺次用1N HCl和饱和NaHCO3水溶液洗涤,再经无水硫酸钠干燥。粗产物在硅胶上经制备TLC纯化,用5%丙酮的氯仿溶液洗脱得到0.022g的2c,为黄色固体。HPLC:100%,2.960min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%MeOH/H2O洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 461.07[M+H]+。原料制备如下。
将[5S-(5α,8α,8aα)]六氢-2-(4-硝基-1-萘基)-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-7(8H)-甲酸,1,1-二甲基乙酯(2c(2))(0.160g,0.37mmol)溶解于二氯甲烷(5.0mL)中,在25℃下,加入TFA(1.5mL)。1.5小时后,真空浓缩反应物,然后再溶解于二氯甲烷中。将该溶液用饱和NaHCO3水溶液洗涤。将水层用二氯甲烷(3×25mL)提取。然后将合并的有机相用无水硫酸钠干燥。真空浓缩得到0.115g的2c(1),为黄色固体。HPLC:93%,1.747min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%MeOH/H2O洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 369.07[M+MeOH]+。
[5S-(5α,8α,8aα)]六氢-2-(4-硝基-1-萘基)-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-7(8H)-甲酸,1,1-二甲基乙酯(2c(2))
将2a(1)(0.220g,0.856mmol)加入到新制活化4_分子筛(0.300g)的无水甲苯(10.0mL)混悬液中。向该混合液中加入4-硝基萘-1-异氰酸酯(0.214g,1.0mmol)。在25℃下搅拌14小时后,加入DBU(0.166ml,1.11mmol),在80℃下,将反应物加热2小时。2小时后,将反应物冷却至25℃,然后倒入1N HCl(50mL)中。将该溶液用二氯甲烷(3×30mL)提取,合并的有机相经无水硫酸钠干燥。粗产物经SiO2快速层析纯化,用0-2-6%丙酮的氯仿溶液洗脱,得到0.211g的2c(2),为黄色泡沫状物。HPLC:95%,3.130min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%MeOH/H2O洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 439.19[M+H]+。实施例2d:[5S-(5α,8α,8aα)]-2-(4-氰基-1-萘基)四氢-7-(异噁唑基羰基)-5,8-亚甲基咪唑并[1,5-a]吡嗪-1,3(2H,5H)-二酮(2dLibSyn1),[5S-(5α,8α,8aα)]-2-(4-氰基-1-萘基)六氢-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-7(8H)-甲酸,4-氟苯基酯(2dLibSyn2),[5S-(5α,8α,8aα)]-2-(4-氰基-1-萘基)四氢-7-[(1-甲基-1H-咪唑-4-基)磺酰基]-5,8-亚甲基咪唑并[1,5-a]吡嗪-1,3(2H,5H)-二酮(2dLibSyn3)和[5S-(5α,8α,8aα)]-2-(4-氰基-1-萘基)N-(4-氟苯基)六氢-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-7(8H)-甲酰胺(2dLibSyn4)的制备溶液相库合成法
以下步骤为以溶液相库形式合成本发明SARM的通法。通过该组合方法制备的具体化合物的更详细说明如下。在粗烧结的聚苯乙烯管中,将一系列类似于2c(1)的游离胺原料(0.05mmol,如上所述制备)溶解于二氯甲烷(1.5mL)中。然后向各反应容器中加入N,N-(二异丙基)氨基甲基聚苯乙烯(3.49mmol/g,60mg),接着通过自动合成器加入所需要的酰氯、异氰酸酯、氯甲酸酯或磺酰氯(0.10mmol)的0.5mL二氯乙烷。在25℃下,将反应容器振摇24小时,然后向各反应容器中加入三-(2-氨基乙基)胺聚苯乙烯HL(200-400目,3.3mmol/g,75mg),在25℃下,将反应容器再振摇18小时。将各管中的液体吸至预称重的2.5ml STR管中,将该树脂用二氯甲烷(3×0.25mL)漂洗。然后将该预称重的管浓缩,通过分析HPLC和LC-MS分析。HPLC(Phenomenex-Prime 5μC-18柱,4.6×50mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。
在粗烧结的聚苯乙烯管中,将[5S-(5α,8α,8aα)]-4-(六氢-1,3-二氧代-5,8-亚甲基咪唑并[1,5-a]吡嗪-2(3H)-基)-1-萘甲腈(2d(1))(0.030g,0.094mmol)溶解于二氯甲烷(2.0mL)中。然后向各反应容器中加入N,N-(二异丙基)氨基甲基聚苯乙烯(3.49mmol/g,65mg),接着加入异噁唑酰氯(0.025g,0.19mmol)。在25℃下,将反应管振摇24小时,然后向各反应容器中加入三-(2-氨基乙基)胺聚苯乙烯HL(200-400目,3.3mmol/g,75mg),在25℃下,振摇18小时。将各管中的液体吸至预称重的2.5ml STR管中,将该树脂用二氯甲烷(3×0.25mL)冲洗。真空浓缩得到粗品2dLiSyn1(0.058g),为黄色固体。不必纯化。HPLC:100%,2.237min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 414.11[M+H]+。
在粗烧结的聚苯乙烯管中,将2d(1)(0.030g,0.094mmol)溶解于二氯甲烷(2.0mL)中。然后向各反应容器中加入N,N-(二异丙基)氨基甲基聚苯乙烯(3.49mmol/g,65mg),接着加入氯甲酸4-氟苯基酯(0.033g,0.19mmol)。在25℃下,将反应管振摇24小时,然后向各反应容器中加入三-(2-氨基乙基)胺聚苯乙烯HL(200-400目,3.3mmol/g,75mg),在25℃下,振摇18小时。将各管中的液体吸至预称重的2.5mlSTR管中,将该树脂用二氯甲烷(3×0.25mL)冲洗。真空浓缩得到粗品2dLibSyn2(0.053g),为黄色固体。不必纯化。HPLC:93%,2.987min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 457.07[M+H]+。
[5S-(5α,8α,8aα)]-2-(4-氰基-1-萘基)四氢-7-[(1-甲基-1H-咪唑-4-基)磺酰基]-5,8-亚甲基咪唑并[1,5-a]吡嗪-1,3(2H,5H)-二酮(2dLibSyn3)
在粗烧结的聚苯乙烯管中,将2d(1)(0.030g,0.094mmol)溶解于二氯甲烷(2.0mL)中。然后向各反应容器中加入N,N-(二异丙基)氨基甲基聚苯乙烯(3.49mmol/g,65mg),接着加入咪唑磺酰氯(0.034g,0.19mmol)。在25℃下,将反应管振摇24小时,然后向各反应容器中加入三-(2-氨基乙基)胺聚苯乙烯HL(200-400目,3.3mmol/g,75mg),在25℃下,振摇18小时。将各管中的液体吸至预称重的2.5mlSTR管中,将该树脂用二氯甲烷(3×0.25mL)冲洗。真空浓缩得到粗品2dLibSyn3(0.043g),为黄色固体。不必纯化。HPLC:70%,1.603min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 463.07[M+H]+。
在粗烧结的聚苯乙烯管中,将2d(1)(0.030g,0.094mmol)溶解于二氯甲烷(2.0mL)中。然后向各反应容器中加入N,N-(二异丙基)氨基甲基聚苯乙烯(3.49mmol/g,65mg),接着加入异氰酸4-氟苯基酯(0.026g,0.19mmol)。在25℃下,将反应管振摇24小时,然后向各反应容器中加入三-(2-氨基乙基)胺聚苯乙烯HL(200-400目,3.3mmol/g,75mg),在25℃下,振摇18小时。将各管中的液体吸至预称重的2.5mlSTR管中,将该树脂用二氯甲烷(3×0.25mL)冲洗。真空浓缩得到粗品2dLibSyn4(0.058g),为黄色固体。不必纯化。HPLC:100%,2.890min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 456.4[M+H]+。实施例2e:(3aα,4β,7β,7aα)-4-(八氢-4,7-二甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基)-2-(三氟甲基)苄腈(2e)的制备(3aα,4β,7β,7aα)-六氢-4,7-环氧-异苯并呋喃-1,3-二酮(2e(1))
将新蒸馏的二甲基呋喃(1.60mL,15.3mmol)溶解于CH2Cl2(2.0mL)中,加入马来酸酐(1.0g,10.2mmol)。在25℃下,将反应物搅拌16小时,然后真空浓缩得到黄色固体。将该固体溶解于乙酸乙酯(30mL)中,加入Pd/C(10%Pd,0.200g)。然后通过氢气球通入氢气,将反应物搅拌24小时。通过硅藻土过滤除去Pd,用EtOAc漂洗,接着真空浓缩得到2e(1)(1.69g),为白色固体。二维NOE测定确证其结构为2e(1)。
(3aα,4β,7β,7aα)-4-(八氢-4,7-二甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基)-2-(三氟甲基)苄腈(2e)
在密封管中,将2e(1)(640mg,3.44mmol,1.07eq)和TsOH(约10mg)的甲苯(5mL)溶液加热2日。将反应混合物冷却至室温,然后减压浓缩。经硅胶快速层析纯化,用50%EtOAc/己烷洗脱得到400mg(1.10mmol,34%)的2e,为白色固体。HPLC:99%,3.04min(保留时间)(YMCS5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ESI):m/z382.2[M+NH4]+。实施例2f:(3aα,4β,7β,7aα)-4-[4-[2-(4-氟苯氧基)乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2f)的制备
在室温、惰性气体中,将DEAD(0.06mL,0.380mmol,1.5eq)加入到三苯膦(100mg,0.380mmol,1.5eq)的THF(1.3mL)溶液中。搅拌10分钟后,一次加入4-氟苯酚(43mg,0.380mmol,1.5eq)。将该反应混合液搅拌5分钟,加入(3aα,4β,7β,7aα)-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2f(1))(100mg,0.254mmol,1eq),继续搅拌3.5小时。经硅胶快速层析纯化,用50%EtOAc/己烷洗脱,接着进行制备层析[HPLC:11.93min(保留时间)(YMC S5 ODS柱,20×100mm,用含有0.1%TFA的0-100%甲醇水溶液洗脱10分钟;流速20mL/min,检测波长220nm)]得到72mg(58%)的固体2f。HPLC:99%,3.74min(保留时间)(YMC S5ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ESI):m/z 487.1[M-H]-。
原料2f(1)制备如下:
在0℃、惰性气体中,将n-BuLi(83mL,133.0mmol,1.2eq,1.6M己烷液)加入到搅拌的2-甲基呋喃(10mL,110.8mmol,1eq)的THF(85mL)溶液中。室温下,将反应混合液搅拌4小时,然后冷却至0℃。滴加环氧乙烷(8.3mL,166.3mmol,1.5eq),将反应混合液温热至室温过夜。用饱和NH4Cl水溶液猝灭,分离得到的溶液层,将水层用Et2O(2X)提取。合并的有机层经Na2SO4干燥,减压浓缩。在大气压力下蒸馏(170-185℃),得到10.13g(80.3mmol,72%)的5-甲基-2-呋喃乙醇(2f(2)),为浅黄色油状物:
在室温下,将2f(2)(252mg,2mmol,1eq)和4-(2,5-二氢-2,5-二氧代-1H-吡咯-1-基)-3-三氟甲基苄腈(798mg,3mmol,1.5eq)的CH2Cl2(10mL)溶液搅拌2日。将该反应混合液减压浓缩。经硅胶快速层析纯化,用65%EtOAc/己烷洗脱得到217mg纯的(3aα,4β,7β,7aα)-4-[1,3,3a,4,7,7a-六氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2f(3A))、73mg纯的(3aα,4α,7α,7aα)-4-[1,3,3a,4,7,7a-六氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2f(3B))和310mg的2f(3A)和2f(3B)的混合物。所有这三部分都为白色固体,总分离率为600mg(1.53mmol,76.5%)。2f(3A):HPLC:90%,2.56min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。2f(3B):HPLC:90%,2.56min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。
在室温、氢气气氛下,将2f(3A)(0.2g,0.51mmol,1eq)和10%Pd/C(约43mg)的EtOH(12mL)溶液搅拌2小时。将反应混合物通过硅藻土过滤,减压浓缩得到0.2g(0.51mmol,100%)白色固体的2f(1)。HPLC:95%,2.59min(保留时间)(YMC S5 ODS柱,4.6×50mm;用含0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ESI):m/z 394.97[M+H]+。实施例2g:(3aα,4β,7β,7aα)-4-[4-(2-溴乙基)八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2g)的制备
在0℃下,将2f(1)(495mg,1.26mmol,1eq)和吡啶(0.1ml,1.26mmol,1eq)的CH2Cl2(2mL)溶液加入到Ph3PBr2(636mg,1.51mmol,1.2eq)的CH2Cl2(2mL)溶液中。室温下,将反应混合物搅拌3小时,然后减压除去溶剂。将得到的残留物用10ml的EtOAc-己烷(6∶4)分次洗涤2X,合并的洗液经硅胶快速层析纯化,用60%EtOAc/己烷洗脱,得到390mg(0.85mmol,67.7%)的白色固体2g。HPLC:99%,3.51min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ESI):m/z 456.7[M-H]-。实施例2h:(3aα,4β,7β,7aα)-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2h)的制备
将(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2h(1))(0.031g,0.061mmol)溶解于THF(0.5mL)中,然后转移至聚丙烯容器中,接着冷却至0℃。然后加入HF·吡啶(约47%HF,0.1mL)。15分钟后,通过LC确定反应完成,然后倒入冷的饱和NaHCO3水溶液中。将该混合液用CH2Cl2(3×10mL)提取。将合并的有机层用1N HCl(1×20mL)洗涤,经无水Na2SO4干燥。分离得到黄色油状物的2h。不必纯化。
HPLC:95%,2.59min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ESI):m/z 394.97[M+H]+。
原料2h(1)制备如下:
向5-甲基-2-呋喃乙醇2f(2)(2.00g,15.9mmol)的DMF(50mL)溶液中,顺次加入咪唑(1.62g,23.9mmol)和叔丁基二甲硅烷基氯(2.63g,17.5mmol)。25℃下2小时后,将反应物倒入乙醚(300mL)中,用水(1×100mL)、1N HCl(1×100mL)、水(1×100mL)、盐水(1×50mL)顺次洗涤,经无水MgSO4干燥。粗产物2-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-5-甲基呋喃(2h(2))经LCMS和NMR分析,测得其纯度足以直接进行下一步反应。HPLC:95%,4.347min(保留时间)(YMC S5ODS柱,4.6×50mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm):
将2h(2)(4.0g,18.9mmol)和马来酸酐(1.42g,14.51mmol)溶解于二氯乙烷(10mL)中,在25℃下,搅拌60小时。然后真空除去挥发物,将得到的橙色油状物溶解于无水乙醇(50mL)中,加入Pd/C(10%Pd,1.00g)。然后通过氢气球通入氢气。3小时后,通过硅藻土过滤反应物,用EtOAc冲洗,真空浓缩。粗品酸酐经SiO2快速层析纯化,用丙酮/氯仿(0-2-4%丙酮)洗脱得到1.30g澄清油状物的(3aα,4β,7β,7aα)-4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]六氢-7-甲基-4,7-环氧-1H-异苯并呋喃-1,3(2H)-二酮(2h(3)),以及3.00g原料2-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-5-甲基呋喃。经质子NMR光谱鉴别显示只有外向异构体。1H NMR,400MHz,CDCl3,3.83(2H,t,J=6.0Hz),3.22(1H,d,J=8.2Hz),3.06(1H,d,J=8.2Hz),1.70-2.25(6H,m),1.55(3H,s),0.82(9H,s),0.00(6H,s):
在密封管中,将2h(3)(0.250g,0.8mmol)和4-氨基-2-三氟甲基苄腈(0.124g,0.668mmol)混悬于无水甲苯(2.0mL)中。然后加入MgSO4(0.200g)和三乙胺(0.5mL),将该管密封,置于125℃的油浴中。40小时后,将反应物冷却至25℃,过滤,真空浓缩。粗产物经SiO2快速层析纯化,用CH2Cl2洗脱,得到0.111g黄色固体的2h(1)。HPLC:92%,4.203min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ESI):m/z 531.1[M+Na]+。实施例2i:[3aR-(3aα,4β,7β,7aα)]-4-[八氢-4-甲基-1,3-二氧代-7-[2-[4-(三氟甲基)苯氧基]乙基]-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2iA),较快洗脱的对映体;[3aS-(3aα,4β,7β,7aα)]-4-[八氢-4-甲基-1,3-二氧代-7-[2-[4-(三氟甲基)苯氧基]乙基]-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2iB),较慢洗脱的对映体的制备
根据2f所述合成的外消旋化合物,可通过手性正相液相色谱,拆分成各自的对映体。将Chiralpak AD柱(50×500mm)用85%己烷/7.5%甲醇/7.5%乙醇洗脱,50mL/min。在220nm处进行紫外检测。经分析性手性正相色谱发现:较快洗脱的异构体2iA(保留时间=55.86min)具有95.8%ee([α]D 25=-53.02°,C=3.134mg/cc(CH2Cl2)),较慢洗脱的异构体2iB(保留时间=62.86min)具有86%ee([α]D 25=+48.74°,C=2.242mg/cc(CH2Cl2))。实施例2j:(aR)-α-甲氧基苯乙酸,2-[(3aα,4β,7β,7aα)-2-(4-氰基-1-萘基)八氢-7-甲基-1,3-二氧代-4,7-环氧-4H-异吲哚-4-基]乙酯(2j)的制备(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2j(1))
在115℃下,将4-氨基-1-萘甲腈(19.2g,114mmol)和马来酸酐(14.0g,113mmol)的AcOH(230mL)溶液加热12小时。冷却至室温后,减压浓缩反应混合物,然后用CH2Cl2(2.5L)稀释。将有机层用水(3L)洗涤3X,用饱和NaHCO3水溶液(1L)洗涤1X,再用盐水(1L)洗涤1X,经MgSO4干燥,减压浓缩至约200mL。经阳离子交换树脂(60g,CUBX13M6,United Chemical Techmologies)纯化,用CH2Cl2洗脱,得到25.0g(88%)黄色固体的4-(2,5-二氢-2,5-二氧代-1H-1-基)-1-萘甲腈:HPLC:96%,2.48min(保留时间)(Phenomenex-Prime S5-C18柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 249.25[M+H]+。
在密封管中,将4-(2,5-二氢-2,5-二氧代-1H-1-基)-1-萘甲腈(1.00g,4.03mmol)混悬于苯(6.0mL)中,加入2h(2)(1.11g,5.24mmol)。在60℃下,将反应物加热16小时,然后冷却至25℃。真空除去苯,得到黄色固体。将该固体溶解于乙酸乙酯(40mL)中,加入Pd/C(10%Pd,0.300g)。然后通过氢气球通入氢气。4小时后,通过硅藻土过滤反应物,用EtOAc冲洗。真空浓缩得到浅黄色固体。经硅胶快速层析纯化,用丙酮/氯仿(0-1.5-3.0%丙酮)洗脱得到2j(1)(1.53g),为黄色泡沫状物。HPLC:86%,4.173min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。(3aα,4β,7β,7aα)-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2j(2))
将2j(1)(1.37g,2.97mmol)溶解于THF(8.0mL)中,然后转移至聚丙烯瓶中,接着冷却至0℃。然后加入HF·吡啶(2.0mL)。20分钟后,将反应物小心倒入冷的饱和NaHCO3水溶液中,用CH2Cl2(3×30mL)提取。然后将有机层用1N HCl洗涤,经无水Na2SO4干燥。真空浓缩得到黄色泡沫状物的2j(2)(0.99g),不必再纯化。HPLC:96%,2.443和2.597(阻转异构体)min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 399.02[M+Na]+。
(aR)-α-甲氧基苯乙酸,2-[(3aα,4β,7β,7aα)-2-(4-氰基-1-萘基)八氢-7-甲基-1,3-二氧代-4,7-环氧-4H-异吲哚-4-基]乙酯(2j)
将2j(2)(0.200g,0.575mmol)加入到WSDCC(0.138g,0.719mmol)和(R)-扁桃酸(0.096g,0.575mmol)的二氯甲烷(6.0mL)溶液中。加入4-DMAP(0.005g)。在25℃下,将反应物搅拌4小时。然后将该混合物用二氯甲烷稀释,用1N HCl(2×10mL)和碳酸氢钠(1×10mL)洗涤,经无水硫酸钠干燥。真空浓缩,得到2j(0.220g),为黄色固体。不再纯化。HPLC:100%,3.283min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 547.26[M+Na]+。实施例2k:(3aα,4β,7β,7aα)-7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]六氢-5-羟基-4-甲基-2-(4-硝基-1-萘基)-4,7-环氧-1H-异吲哚-1,3(2H)-二酮(2k)的制备
(3aα,4β,7β,7aα)-4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-3a,4,7,7a-四氢-7-甲基-2-(4-硝基-1-萘基)-4,7-环氧-1H-异吲哚-1,3(2H)-二酮(2k(1))
在60℃下,将2h(2)(455mg,1.894mmol)和1-[4-硝基萘基]-1H-吡咯-2,5-二酮(254mg,0.947mmol)的苯(2mL)溶液加热过夜。1-[4-硝基萘基]-H-吡咯-2,5-二酮按2j(1)中说明制备。将该反应混合液减压浓缩,得到粗品2h(2),为棕色固体,不经进一步纯化直接用于下一步。
(3aα,4β,5β,7β,7aα)-7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]六氢-5-羟基-4-甲基-2-(4-硝基-1-萘基)-4,7-环氧-1H-异吲哚-1,3(2H)-二酮(2k)
将BH3·THF(0.95mL,0.95mmol,1M的THF溶液)加入到0℃下的粗品2k(1)(0.95mmol)的THF(2mL)溶液中。待2k(1)消耗完毕后,将反应混合液减压浓缩。然后将得到的残留物溶于甲苯(2mL)中,加入Me3NO(71mg,2.84mmol),将该混合液加热回流过夜。然后将反应混合液冷却至室温,加入到水中,用EtOAc(3x)提取。合并的有机层经MgSO4干燥,减压浓缩。经SiO2快速层析纯化,用75%EtOAc/30%己烷混合物洗脱,得到130.2mg(26%)的2k,为棕色固体。HPLC:94%,3.92min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 527.5[M+H]+。实施例2l:(3aα,4β,5β,7β,7aα)-六氢-5-羟基-7-(2-羟基乙基)-4-甲基-2-(4-硝基-1-萘基)-4,7-环氧-1H-异吲哚-1,3(2H)-二酮(2l)的制备
将TBAF(0.3mL,0.296mmol,1M的THF溶液)和HF(0.3mL,50%水溶液)的乙腈(6mL)混合液加入到0℃下的2k(104mg,0.197mmol)的THF(2mL)溶液中。室温下,将反应混合液搅拌过夜。待通过TLC证实原料消耗完毕后,加入H2O和EtOAc,分层。将水层用EtOAc(1x)提取,合并的有机层用水(1x)和盐水(1x)洗涤,经Na2SO4干燥,减压浓缩。经SiO2快速层析纯化,用5%MeOH/CH2Cl2洗脱,得到61.2mg(75%)的2l,为黄色固体。HPLC:99%,2.47min(保留时间)(YMC S5ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 411.2[M-H]-。实施例2m:(3aα,4β,5β,7β,7aα)-7-[2-(4-氟苯氧基)乙基]六氢-5-羟基-4-甲基-2-(4-硝基-1-萘基)-4,7-环氧-1H-异吲哚-1,3(2H)-二酮(2m)的制备
将DBAD(37.7mg,0.164mmol,1.5eq)加入到PPh3(43mg,0.164mmol,1.5eq)的THF(1mL)溶液中。搅拌10分钟后,加入4-氟苯酚(18.3mg,0.164mmol,1.5eq),再将该反应混合液搅拌5分钟。加入2l(45mg,0.109mmol,1eq)的THF(1mL)溶液,室温下,将反应混合液搅拌过夜。HPLC表明该粗反应混合液中包含大多数的原料二醇(21)因此将该混合液加入到室温下的预形成的PPh3(86mg,3eq)、DBAD(75.4mg,3eq)和苯酚(36.6mg,3eq)的THF(4mL)溶液中。继续搅拌直至HPLC表明2l消耗完毕。减压浓缩反应物。经制备层析纯化[HPLC:15.2min(保留时间)(YMC S5 ODS A柱,20×100mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱15分钟;流速20mL/min,检测波长220nm)]得到25.0mg(45%)的浅黄色固体2m。HPLC:99%,3.53min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z505.2[M-H]-。
将DBAD(37.7mg,0.164mmol)加入到PPh3(43mg,0.164mmol)的THF(1mL)溶液中。搅拌10分钟后,加入4-氟苯酚(18.3mg,0.164mmol),再将该反应混合液搅拌5分钟。加入化合物2l(45mg,0.109mmol)的THF(1mL)溶液,室温下,将反应混合液搅拌过夜。HPLC表明该粗反应混合液中包含大多数的原料二醇(化合物2l),因此将该混合液加入到室温下的预形成的PPh3(86mg)、DBAD(75.4mg)和苯酚(36.6mg)的THF(4mL)溶液中。继续搅拌直至HPLC表明2l消耗完毕。减压浓缩反应物。经制备层析纯化[HPLC:15.2min(保留时间)(YMC S5ODS A柱,20×100mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱15分钟;流速20mL/min,检测波长220nm)]得到25.0mg(45%)的浅黄色固体2m。HPLC:99%,3.53min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 505.2[M-H]-。实施例2n:[3aR-(3aα,4β,7β,7aα)]-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2nA)&[3aS-(3aα,4β,7β,7aα)]-4-[八氢-4-(2-羟基乙基)-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2nB)的制备
通过制备性手性HPLC(CHIRALPAK AD 5×50cm柱;用20%MeOH/EtOH(1∶1)的庚烷(等度)洗脱,流速50mL/min,220nm),将外消旋体2j(2)拆分,洗脱较快的是化合物2nA(手性HPLC:13.54min;CHIRALPAK AD 4.6×250cm柱;用20%MeOH/EtOH(1∶1)的庚烷洗脱,流速1mL/min),洗脱较慢的是化合物2nB(手性HPLC:14.99min;CHIRALPAK AD 4.6×250cm柱;用20%MeOH/EtOH(1∶1)的庚烷洗脱,流速1mL/min)。化合物2nA和2nB的绝对构型还未确定。为简化命名,本发明指定化合物2nA具有“R”构型,而化合物2nB本发明指定具有“S”构型。本发明指定源于2nA的纯对映体产物具有“R”构型,而源于2nB的纯对映体产物本发明被指定具有“S”构型。实施例2o:[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(3-氟苯氧基)乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2oA)&[3aS-(3aα,4β,7β,7aα)-4-[4-[2-(3-氟苯氧基)乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2oB)的制备
向三苯膦(0.0524g,0.20mmol)的THF(2.0mL)溶液中,加入DBAD(0.046g,0.2mmol)。10分钟后,加入3-氟苯酚(0.018mL,0.2mmol)。再经10分钟后,加入对映体纯的2nA(0.050g,0.133mmol)。在25℃下3小时后,真空浓缩反应物,经制备HPLC(YMC S5 ODS柱,20×100mm,用含有0.2%TFA的10-90%甲醇水溶液洗脱15分钟;流速20mL/min,检测波长220nm)纯化,得到0.031g白色固体的2oA化合物。用对映体纯的2nB重复该过程,得到2oB。2oA:HPLC:100%,3.80min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 471.65[M+H]+,[α]D 25=-47.371(c=4.412mg/cc,CH2Cl2)。2oB:HPLC:100%,3.80min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 471.65[M+H]+,[α]D 25=+24.3(c=4.165mg/cc,CH2Cl2)。实施例2p:[3aS-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2pA)&[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2pB)的制备
(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-1,3,3a,4,7,7a-六氢-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2p(1))
将4-(2,5-二氢-2,5-二氧代-1H-1-基)-1-萘甲腈(18.3g,68.7mmol)加入到2h(2)(26.6g,110.6mmol)的苯(75mL)溶液中,加热至60℃过夜。冷却至室温后,将反应混合液减压浓缩。在0℃、搅拌下,将该残留物用MeOH(250mL)处理10分钟。将得到的固体过滤,用冷MeOH(2×10mL)洗涤,干燥得到26.7g(79.5%)黄色固体的2p(1)。以上固体经HPLC分析得出纯度为95%(HPLC条件:95%,2.48min(Phenomenex-Prime S5-C18柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm))。然后将滤液减压浓缩,将得到的固体层析,用3%丙酮/CHCl3洗脱,再得到4.36g的2p(1),总收率为92.5%。
(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2p(2))
将2p(1)(10g,20.46mmol)和 RhCl(PPh3)3(0.947mg,1.02mmol)混合物排空,然后通入氩气(3X)。加入THF(200mL),待所有的颗粒溶解后,立即慢慢滴加儿茶酚硼烷(4.4mL,40.93mmol)。当通过HPLC确定产物停止生成后,将反应混合液冷却至0℃,用磷酸盐缓冲液(300mL,pH7.2)猝灭,然后加入EtOH(130mL)和H2O2(300mL,30%水溶液)。待硼烷消耗完毕后,将该混合液用CH2Cl2(3X)提取,合并的有机层用1N NaOH、10%NaHSO3水溶液(1∶1,1X)和盐水(1X)洗涤。将合并的洗液用CH2Cl2(1X)提取,合并的有机层经Na2SO4干燥。经硅胶快速层析纯化,用10%-30%丙酮/氯仿梯度洗脱25分钟,得到7.1g(68%)的2p(2),为浅黄色固体。HPLC条件:98%,3.82min(Phenomenex-Prime S5-C18柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。
[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2p(3A))和[3aR-(3aα,4β,5β,7β,7aα)-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2p(3B))
通过手性正相液相色谱,将外消旋化合物2p(2)拆分成单一对映体。采用Chiralpak OD柱(50×500mm),用13%EtOH/己烷洗脱99分钟,流速50mL/min,检测波长220nm。较快洗脱的异构体2p(3A)保留时间为45min,较慢洗脱的异构体2p(3B)保留时间为66min。
[3aS-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2pA)和[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2pB)
将2p(3A)(0.84g,2.14mmol)溶解于2%12N HCl/EtOH(20mL)中,搅拌5分钟,减压浓缩。经硅胶快速层析纯化,用5%-10%MeOH/CH2Cl2洗脱,得到0.57g(88%)的2pA。通过分析性手性正相液相色谱分析,发现源于较快洗脱的异构体(2p(3A))的2pA为99.7%ee。HPLC条件:99.7%,2.17min(Chiralcel OJ柱44.6×250mm,10微米,40℃,等度80%庚烷/20%EtOH/MeOH(1∶1),流速1.0mL/min,检测波长288nm)。
将2p(3B)(0.86g,2.19mmol)溶解于2%12N HCl/EtOH(20mL)中,搅拌5分钟,减压浓缩。经硅胶快速层析纯化,用5%-10%MeOH/CH2Cl2洗脱,得到0.60g(90%)的2pB。通过分析性手性正相液相色谱分析,发现源于较慢洗脱的异构体(2p(3B))的2pB为87.1%ee。HPLC条件:87.1%,18.4min(Chiralcel OJ柱44.6×250mm,10微米,40℃,等度80%庚烷/20%EtOH/MeOH(1∶1),流速1.0mL/min,检测波长288nm)。
化合物2pA和2pB的绝对构型未确定。为简化命名,本发明指定化合物2pA具有“S”构型,而化合物2pB本发明指定具有“R”构型。本发明指定源于化合物2pA的纯对映体产物具有“S”构型,而源于2pB的纯对映体产物本发明指定具有“R”构型。实施例2q:[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-氰基苯氧基)乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2qA)和[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(4-氰基苯氧基)乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2qB)的制备
将DBAD(26mg,0.115mmol)加入到PPh3(30mg,0.115mmol)的THF(0.65mL)溶液中。搅拌10分钟后,加入4-氰基苯酚(13.6mg,0.115mmol),再将该反应混合液搅拌5分钟。加入化合物2pA(30mg,0.076mmol),将反应混合液在室温下搅拌1小时。将该反应液减压浓缩。经硅胶快速层析纯化,用30%丙酮/70%氯仿洗脱,得到23.1mg(0.047mmo],61.7%)的化合物2qA。HPLC条件:95%,3.06min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 494.09[M+H]+。[α]D=53.30°,C=4.5mg/cc(THF),589nm)。
将DBAD(26mg,0.115mmol)加入到PPh3(30mg,0.115mmol)的THF(0.65mL)溶液中。搅拌10分钟后,加入4-氰基苯酚(13.6mg,0.115mmol),再将该反应混合液搅拌5分钟。加入化合物2pB(30mg,0.076mmol),将反应混合液在室温下搅拌1小时。将该反应液减压浓缩。经硅胶快速层析纯化,用30%丙酮/70%氯仿洗脱,得到20.3mg(0.041mmol,54.2%)的化合物2qB。HPLC条件:90%,3.07min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 494.09[M+H]+。[α]D=-42.87°,C=6.6mg/cc(THF),589nm)。实施例2r:(3aα,4β,7β,7aα)-4-[4-[2-[(6-氯-1,2-苯并异噁唑-3-基)氧基]乙基]八氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2r)的制备
向PPh3(52mg,0.20mmol)的0.5ml THF溶液中,一次性加入固体DBAD(46mg,0.20mmol)。将得到的混合液搅拌10分钟,然后加入6-氯-3-羟基-1,2-苯并异噁唑(34mg,0.20mmol)。继续搅拌10分钟,然后通过插管加入2j(2)(50mg,0.13mmol)的0.5mL THF溶液。室温下,将得到的混合液搅拌24小时,浓缩,经制备反相HPLC(YMC S5ODS柱,20×100mm,用含有0.1%TFA的30-100%甲醇水溶液洗脱10分钟,流速20mL/min)纯化,得到白色固体。将得到的固体溶解于CH2Cl2中,用饱和NaHCO3溶液洗涤,经Na2SO4干燥,浓缩得到50mg(71%)的2r,为无色油状物。HPLC条件:26%,3.89min和74%,4.02min(阻转异构体混合物,保留时间)(YMC S5 ODS柱,4.6×50mmBallistic,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 528.4[M+H]+。实施例2s:(3aα,4β,7β,7aα)-4-[八氢-4-甲基-7-[2-[(6-硝基-1H-吲唑-3-基)氧基]乙基]-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2s)的制备
向2j(2)(50mg,0.13mmol)的甲苯(1mL)溶液中,加入ADDP(50mg,0.20mmol)、6-硝基-3-吲唑啉酮(36mg,0.20mmol)和n-Bu3P(50μL,0.2mmol)。在80℃下,将得到的混合液加热24小时,浓缩,经制备反相HPLC(YMC S5 ODS柱,20×100mm,用含有0.1%TFA的30-100%甲醇水溶液洗脱10分钟,流速20mL/min)和快速层析(硅胶,25%丙酮的氯仿液)联合纯化,得到17mg(25%)的黄色固体2s。HPLC:24%,3.60min和76%,3.74min(阻转异构体混合物,保留时间)(YMC S5 ODS柱,4.6×50mm Ballistic,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 537.6[M+H]+。实施例2t:[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(1,2-苯并异噁唑-3-基氧基)乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2t)的制备
根据2r给出的方法,使PPh3(47mg,0.18mmol)、DBAD(41mg,0.18mmol)、3-羟基-1,2-苯并异噁唑(24mg,0.18mmol)和化合物2pA(35mg,0.09mmol)反应。经反相HPLC(YMC S5 ODS柱,20×100mm,用含有0.1%TFA的30-100%甲醇水溶液洗脱10分钟,流速20mL/min)纯化,得到白色固体。将得到的固体溶解于CH2Cl2中,用饱和NaHCO3溶液洗涤,经Na2SO4干燥,浓缩得到29mg(64%)的2t,为无色油状物。HPLC条件:96%,3.29min(阻转异构体混合物,保留时间)(YMCS5 ODS柱,4.6×50mm Ballistic,用含有0.2%磷酸的0-100%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z510.2[M+H]+。实施例2u:[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(1,2-苯并异噁唑-3-基氧基)乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2u)的制备
根据2r给出的方法,使PPh3(47mg,0.18mmol)、DBAD(41mg,0.18mmol)、3-羟基-1,2-苯并异噁唑(24mg,0.18mmol)和化合物2pB(35mg,0.09mmol)反应。经反相HPLC(YMC S5 ODS柱,20×100mm,用含有0.1%TFA的30-100%甲醇水溶液洗脱10分钟,流速20mL/min)纯化,得到白色固体。将得到的固体溶解于CH2Cl2中,用饱和NaHCO3溶液洗涤,经Na2SO4干燥,浓缩得到23mg(51%)的2u,为无色油状物。HPLC条件:95%,3.29min(阻转异构体混合物,保留时间)(YMCS5 ODS柱,4.6×50mm Ballistic,用含有0.2%磷酸的0-100%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z510.4[M+H]+。实施例2v:(3aα,4β,7β,7aα)-4-[4-[2-(4-氰基苯氧基)乙基]-7-乙基八氢-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2v)的制备2-乙基-5-(2-羟基乙基)呋喃(2v(1))
在-25℃下,将n-BuLi(2.5M己烷液,4.4mL,11mmol)加入到2-乙基呋喃(1.05mL,10mmol)的THF(10mL)溶液中。将该混合液温热至室温,搅拌3小时。在-78℃下,加入环氧乙烷(0.75mL)。在-15℃下,将反应物搅拌0.5小时,然后室温下搅拌过夜。加入饱和NH4Cl水溶液,将该混合液用乙醚(3X)提取。将合并的提取液用水(1X)和盐水(1X)洗涤,经Na2SO4干燥。经硅胶快速层析纯化,用30%EtOAc/70%己烷洗脱,得到1.12g(8.02mmol,80.2%)黄色油状物的2v(1)。
在60℃下,将2v(1)(280mg,2.00mmol)和4-(2,5-二氢-2,5-二氧代-1H-1-基)-1-萘甲腈(496mg,2.00mmol)的苯(2mL)溶液搅拌2小时。将反应混合液减压浓缩。黄色固体2v(2)直接用于下一步。
(3aα,4β,7β,7aα)-4-[4-乙基八氢-7-(2-羟基乙基)-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2v(3))
在室温、氢气气氛下,将2v(2)(764mg,1.97mmol)和10%Pd/C(约115mg)的EtOAc(36mL)溶液搅拌2小时。将反应混合液通过硅藻土过滤,减压浓缩得到779mg的粗品2v(3)。该粗产物经硅胶快速层析纯化,用70%EtOAc/30%己烷洗脱得到235mg(0.6mmol,30.1%)的2v(3)。HPLC条件:99%,2.84min(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 391.12[M+H]+。
(3aα,4β,7β,7aα)-4-[4-[2-(4-氰基苯氧基)乙基]-7-乙基八氢-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2v)
将DBAD(44.2mg,0.192mmol)加入到PPh3(50.4mg,0.192mmol)的THF(1mL)溶液中。搅拌10分钟后,加入4-氰基苯酚(23mg,0.192mmol),再将该反应混合液搅拌5分钟。加入2v(3)(50mg,0.128mmol),将反应混合液在室温搅拌2小时。将该反应液减压浓缩。经硅胶快速层析纯化,用40%EtOAc/60%己烷洗脱,得到43mg(0.087mmol,68.4%)白色固体化合物2v。HPLC条件:99%,3.65min(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10%-90%甲醇水溶液洗脱4分钟;检测波长220nm)。MS(ES):m/z 492.16[M+H]+。实施例2w:[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-(乙酰氧基)乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2wA)和[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2wB)的制备
在2L烧瓶中,将化合物2pA和2pB的外消旋混合物(1.90g)溶解于100mL的无水THF中。搅拌下,将无水叔丁基甲醚(900mL)和乙酸乙烯基酯(40mL)转移至该烧瓶中,加入脂酶(20g,II型,粗品,源于猪胰脏,Sigma,Cat#L3126)。室温下,将反应混合物搅拌21小时,然后加入5g脂酶和20mL乙酸乙烯基酯。室温下。将反应物再搅拌19小时,在4℃、无搅拌下,储存36小时,然后再在室温下搅拌22小时(通过手性HPLC测定达到所要求的%ee)。为监测该反应,抽取200uL该混合物,离心。在氮气下干燥上清液(100uL),将得到的残留物溶解于100uL的EtOH中,经HPLC分析:
1)反相HPLC:柱,YMC-ODS,AQ 150×4.6;流速,1.2mL/min;
进样量,10uL
溶剂A:1mM HCl水溶液;溶剂B,MeCN;检测波长:300nm
梯度:
时间(min)0 8 8.5 9.5 10 12
B% 30 60 85 85 30 30
2)手性HPLC:柱,CHIRALCEL OJ 4.6×250mm
流动相,己烷/MeOH/EtOH(8∶1∶1)
流速,1mL/min;进样量,20uL
检测波长:220和300nm
温度:25℃&40℃
(测定反应混合物的ee%)
过滤除去所述酶,真空浓缩滤液。将得到的混合物溶于CHCl3中,吸附于硅胶上(63-200微米)。将这些固体加于包含5cm硅胶床高度(25-40微米)的VLC漏斗(3cm I.D.,VLC是采用在底部具有24/40结合点的玻璃漏斗真空液相色谱)中,进行梯度洗脱步骤。梯度为前三个馏分100%CHCl3,接着CHCl3-1%MeOH(三个馏分)、CHCl3-2%MeOH(三个馏分)、CHCl3-3%MeOH(三个馏分)、CHCl3-4%MeOH(三个馏分),最后CHCl3-5%MeOH(三个馏分)。至达到CHCl3-3%MeOH时,馏分的体积为100mL,从CHCl3-3%MeOH点开始收集馏分200mL。2wA洗脱在100%CHCl3的最后两馏分中,直至CHCl3-2%MeOH的第一馏分为止。2wB洗脱从CHCl3-2%MeOH的第二馏分开始,直至CHCl3-5%MeOH的第一馏分为止。粗品化合物2wB包含少量的有色杂质,通过Sephadex柱[LH-20浸泡于CHCl3-5%MeOH(2∶1)中,柱(2.5cm I.D.&90cm长)]除去,生成632mg化合物2wB。化合物2wA:HPLC条件:98%,7.2min(方法1),手性HPLC条件:29.0min,25℃(方法2)。化合物2wB:HPLC条件:98%,4.6min(方法1),手性HPLC条件:96%ee,25.7min(25℃)&19.8min℃(40℃)(方法2)。实施例2x:(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-1,3,3a,4,7,7a-六氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈&(3aα,4α,7α,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-1,3,3a,4,7,7a-六氢-7-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2xA&2xB)的制备
将化合物2h(2)(2.00g,8.50mmol)和4-(2,5-二氢-2,5-二氧代-1H-吡咯-1-基)-2-三氟甲基苄腈(1.50g,5.60mmol)在苯(5.0mL)中混合,在60℃下加热14小时,然后冷却至25℃。在40℃下,真空去除溶剂1小时,得到粗产物,经SiO2快速层析纯化,用0.5%EtOAc/CH2Cl2洗脱得到2.0g化合物2xA和1.3g化合物2xB,均为浅棕色固体。化合物2xA:HPLC:95%,4.200min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速:4mL/min,检测波长220nm),MS(ES):m/z 507.1[M+H]+。化合物2xB:HPLC:95%4.20min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速:4mL/min,检测波长220nm),MS(ES):m/z 507.1[M+H]+。实施例2y:[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈&[3aS-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2yA&2yB)的制备
在烧瓶中,将2xA(1.40g,2.77mmol)和 RhCl(PPh3)3(0.128g,0.14mmol)混合。然后将烧瓶排空,充填氩气3次。接着通过注射器加入THF(3.0mL)。待所有的颗粒溶解后,立即滴加儿茶酚硼烷(0.59mL,5.54mmol)。在25℃、氩气下,将反应混合液搅拌30分钟,然后冷却至0℃。加入磷酸盐缓冲液(pH=7,20mL),接着加入EtOH(10mL)、30%H2O2/H2O(2mL)。在0℃下,将反应混合液搅拌3小时,然后用CH2Cl2(3×25mL)提取。合并的有机层用1N NaOH(25mL)、10%Na2SO3(25mL)和盐水(25mL)洗涤。然后将粗产物浓缩,经SiO2快速层析纯化,用2%EtOAc/CH2Cl2-10%EtOAc/CH2Cl2洗脱,得到0.63g浅黄色固体的化合物2yA&2yB的外消旋混合物。HPLC条件:99%,3.867min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速:4mL/min,检测波长220nm),MS(ES):m/z 525.1[M+H]。
通过制备性手性正相HPLC,拆分化合物2yA&2yB的外消旋混合物,采用Chiralpak OD柱(5cm×50cm),用13%溶剂B(EtOH)的溶剂A(己烷)溶液,流速:50mL/min。化合物2yA从34min至38min洗脱出,化合物2yB从44min至49min洗脱出。通过手性HPLC测定对映体过量。化合物2yA:>99%ee(12.576min(保留时间)(ChiralcelOJ柱,4.6×250mm,用等度85%庚烷/15%MeOH/乙醇(1∶1)洗脱;流速:1mL/min,检测波长220nm,40℃)。化合物2yB:99%ee(18.133min(保留时间)(Chiralcel OJ柱,4.6×250mm,用等度85%庚烷/15%MeOH/乙醇(1∶1)洗脱;流速:1mL/min,检测波长220nm,40℃)。
化合物2yA和2yB的绝对构型未确定。为简化命名,本发明指定化合物2yA具有“R”构型,而化合物2yB本发明指定具有“S”构型。本发明指定源于化合物2yA的纯对映体产物具有“R”构型,而源于2yB的纯对映体产物本发明指定具有“S”构型。实施例2z:[3aR-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈&[3aS-(3aα,4β,5β,7β,7aα)]-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2zA&2zB)的制备
将化合物2yA(180mg,0.34mmol)溶解于2%HCl/EtOH(5mL)中。30分钟后,加入饱和NaHCO3,将水层用二氯甲烷(20mL×3)提取,用盐水洗涤,经Na2SO4干燥,得到135mg的化合物2zA。HPLC:99%,2.257min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm)。MS(ES):m/z 411[M+H]+。
用化合物2yB重复以上步骤,以类似收率获得所需要的二醇化合物2zB。实施例2a(i):[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[(5-氯-2-吡啶基)氧基]乙基]八氢-5-羟基-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-2-(三氟甲基)苄腈(2a(i))的制备
将三苯膦(0.026g,0.098mmol)和DBAD(0.023g,0.098mmol)在THF(0.5mL)中混合。将以上混合物反应15分钟后,加入2-羟基-6-氯吡啶(0.016g,0.100mmol),将该混合液搅拌10分钟,加入2zA(0.020g,0.049mmol)。在25℃下,将该反应混合液搅拌2小时,然后通过制备TLC纯化粗产物,用10%丙酮/氯仿洗脱,得到0.014g浅棕色固体的化合物2a(i)。HPLC:100%,3.370min(保留时间)(YMC S5 ODS柱,4.6×50mm,用含有0.1%TFA的10-90%甲醇水溶液洗脱4分钟;流速4mL/min,检测波长220nm),MS(ES):m/z 522.08[M+H]+。实施例2b(i):(3aα,4β,5β,7β,7aα)-4-[4-乙基八氢-5-羟基-7-(2-羟基乙基)-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2b(i)C)的制备叔丁基-[2-(5-乙基-呋喃-2-基)-乙氧基]-二甲基-硅烷(2b(i)A)
将咪唑(255mg,3.75mmol)和TBSCl(414mg,2.75mmol)加入到(2v(1))(350mg,2.5mmol)的DMF(4mL)溶液中。室温下,将该混合物搅拌15小时,然后再加入100mg(0.66mmol)的TBSCl促使反应完成。再搅拌1小时后,将反应混合物用乙醚(100mL)稀释,用水(20mL)、1N HCl(20mL)、水(20mL)和盐水(20mL)洗涤。有机层经Na2SO4干燥,减压浓缩得到509mg黄色油状物的化合物2b(i)A(80.3%)。
(3aα,4β,7β,7aα)-4-[4-[2-[[(1,1-二甲基乙基)二甲硅烷基]氧基]乙基]-4-乙基-1,3,3a,4,7,7a-六氢-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2b(i)B)
在60℃下,将化合物2b(i)A(509mg,2.00mmol)和4-(2,5-二氢-2,5-二氧代-1H-1-基)-1-萘甲腈(498mg,2.00mmol)的苯(2mL)溶液加热18小时。减压浓缩反应混合液,得到992mg(99%)的粗品化合物2b(i)B,不经进一步纯化直接用于下一步反应中。
(3aα,4β,5β,7β,7aα)-4-[4-乙基八氢-5-羟基-7-(2-羟基乙基)-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2b(i)C)
将化合物2b(i)B(992mg,1.98mmol)和RhCl2(PPh3)3(183mg,0.198mmol)混合物排空,充填氩气(3X)。加入THF(20mL),待所有的颗粒溶解后,立即慢慢滴加儿茶酚硼烷(0.42mL,3.96mmol)。当通过HPLC确定产物停止形成后,将反应混合物冷却至0℃,用磷酸盐缓冲液(34mL,pH7.2)猝灭,接着加入EtOH(19mL)和H2O2(2.9mL,30%水溶液)。2小时后,再加入磷酸盐缓冲液(6.8mL,pH7.2)、EtOH(3.8mL)和H2O2(0.6mL)。室温下,将反应混合液搅拌3小时。待硼酸盐中间体消耗完毕后,将该混合液用CH2Cl2(300mL)提取,合并的有机层用1N NaOH、10%NaHSO3和盐水洗涤。合并的有机层经Na2SO4干燥。经硅胶快速层析纯化,用10%MeOH/CH2Cl2洗脱,得到75mg(9.3%)灰色固体的化合物2b(i)C。HPLC条件:97%,2.43min(Phenomenex-prime S5-Cl8柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液洗脱4分钟,检测波长220nm)。MS(ES):m/z 407.18[M+H]+。实施例2c(i):(3aα,4β,5β,7β,7aα)-4-[7-[2-(4-氰基苯氧基)乙基]-4-乙基八氢-5-羟基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2c(i))的制备
将DBAD(39.6mg,0.172mmol)加入到PPh3(45.1mg,0.172mmol)的THF(0.8mL)溶液中。搅拌10分钟后,加入4-氰基苯酚(20.5mg,0.172mmol),再将该反应混合液搅拌5分钟。加入化合物2b(i)C(25.0mg,0.062mmol),室温下,将混合液搅拌2小时。将反应物减压浓缩。经制备TLC纯化,用10%丙酮/氯仿洗脱,得到18.1mg(0.036mmol,57.6%)的化合物2c(i)。HPLC条件:96%,3.15min(YMC S5 ODS柱,4.6×50mm,用含有0.2%磷酸的10-90%甲醇水溶液梯度洗脱4分钟,检测波长220nm)。MS(ES):m/z 508.14[M+H]+。实施例2d(i):(3aα,4β,5β,7β,7aα)-4-[八氢-5-羟基-7-(2-羟基乙基)-4-甲基-1,3-二氧代-4,7-环氧-2H-异吲哚-2-基]-1-萘甲腈(2d(i))
通过生物转化将化合物(2j(1))和(2j(2))转化为化合物2d(i)。化合物2j(1)的微生物羟基化反应步骤1:反应
将一管(约2ml)冰冻的灰色链霉菌(Streptomyces griseus)ATCC10137加入到装有100ml转化培养基的500ml烧瓶中。该转化培养基制备如下:向2升塑料烧杯中,加入20g葡萄糖、5.0g酵母提取物、5.0g大豆粉、5.0g氯化钠、5.0g磷酸氢二钾和1升去离子水,室温下,将该混合液搅拌3-30分钟。然后用1N HCl或1N NaOH,将混合物pH调节至7.0。将得到的混合液加入到500ml烧瓶中(每瓶100ml)。将这些烧瓶用Bio/Wrap盖上,在121℃下高压灭菌15分钟,用前冷却至室温。
将培养物在28℃下并以250rpm孵育3日。将1ml得到的培养物加入到装有100ml转化培养基的500ml烧瓶中,将该烧瓶在28℃下并以250rpm孵育24小时。将10ml得到的培养物转移至50ml烧瓶中,向其中加入1mg化合物2j(1)的0.2ml乙醇溶液。将该烧瓶在28℃下并以250rpm孵育23小时,将该反应培养物用EtOAc(10ml)提取。将该EtOAc提取液在N2下干燥,将残留物溶解于1ml MeOH(反应提取物)中。HPLC分析表明:该反应培养物中化合物2d(i)与化合物2j(1)的峰面积比率约为1.1/1。步骤2:产物分析HPLC
将10μl所述反应提取物注射入HPLC柱(YMC ODS-AQ C-18柱,150×6.0mm i.d.)。将该柱用1mM HCl的水溶液/CH3CN洗脱,流速1.2ml/min:30-60%CH3CN洗脱8分钟,60-85%CH3CN洗脱0.5分钟,85%CH3CN洗脱1分钟,85-30%CH3CN洗脱0.5分钟。在300nm处检测洗脱液。观测到两主峰的峰面积比为1∶1,与化合物2d(i)和(2j(1))的具有相同的UV光谱,保留时间分别为4.55min和7.23min,与化合物2d(i)(4.53min)和(2j(1))(7.2min)的可信样品的保留时间吻合。LC/MS反应提取物:两个UV主峰峰1,Tr 4.68min:391[M+H]+,343,319,303,289峰2,Tr 5.35min:375[M+H]+,345可信样品化合物2d(i),Tr 4.82min:391[M+H]+,343,319,289化合物(2j(1)),Tr 5.48min:375M+H]+,345
本领域技术人员在阅读本公开时将能懂得,还可根据本发明公开的方法,鉴定可用于本发明的其它SARM。例如,可根据下列测定说明,对推测具有选择性调节雄激素受体活性的试验化合物,用激素依赖性肿瘤细胞系(如人或小鼠乳腺肿瘤细胞系)筛选拮抗活性,用另一包含雄激素受体的非肿瘤细胞系(如肌肉、前列腺或精囊细胞系)筛选激动活性。可根据本发明提供的指导,常规进行这些筛选测定。实施例3:AR结合测定
为进行完整细胞结合测定,在37℃下,在装有分别包含增添10%活性碳解吸的CA-FBS(Cocaleco Biologicals)的RPMI 1640或DMEM的96孔微量滴定板中,将人LNCaP细胞(T877A突变AR)或MDA453(野生型AR)培养,以除去可能与细胞受体结合的任何内源性配体。48小时后,或者进行饱和分析以确定逐渐增加的二氢睾丸素[3H]-DHT的Kd,或者进行竞争性结合测定以评估试验化合物与[3H]-DHT竞争的能力。在饱和分析中,将无(总结合)或有(非特异性结合)500倍摩尔过量的非标记DHT存在下的含有[3H]-DHT(浓度范围0.1nM-16nM)的培养基(RPMI 1640或DMEM-0.2%CA-FBS)加入到细胞中。在37℃下4小时后,取各[3H]-DHT浓度下等份的所述总结合培养基测定游离[3H]-DHT的量。除去剩余的培养基,用PBS将细胞洗涤3次,收集至UniFilter GF/B板(Packard)上,加入Microscint(Packard),用Top-Counter(Packard)将板计数以评估结合的[3H]-DHT量。
在饱和分析中,将总结合与非特异性结合之间的差定义为特异性结合。特异性结合可根据Scatchard分析确定[3H]-DHT的Kd值评估。例如,参见D.Rodbard,Mathematics and statistics of ligand assays:an illustrated guide:In:J.Langon and J.J.Clapp,eds.,Ligand Assay,Masson Publishing U.S.A.,Inc.,New York,pp.45-99,(1981),该公开内容结合到本发明中作为参考。
为进行竞争性研究,将包含1nM[3H]-DHT和浓度范围为10-10至10-5M的试验化合物的培养基加入到所述细胞中。每个样本采用一式两份进行测定。在37℃下4小时后,如上所述进行细胞洗涤、收集和计数。将该数据作为保留[3H]-DHT量(试验化合物不存在下对照组的%),标绘出所给定化合物的剂量反应曲线范围内的位置。在进行对数-对数值转化后,定出竞争性配体不存在下抑制50%[3H]-DHT结合的量的试验化合物的浓度(IC50)。通过将Cheng-Prusoff方程用于IC50值,确定KI值,其中:
对非特异性结合校正后,确定IC50值。IC50值定义为降低50%特异性结合所需要的竞争性配体的浓度。MDA453和LNCaP的[3H]-DHT的Kd值分别为0.7和0.2nM。实施例4:人体前列腺细胞增殖测定
还检测了试验化合物对人前列腺癌细胞系增殖的作用。对进行该测定,将MDA PCa2b(一种源于未阉割患者的转移的细胞系)(Navone等,Clin.Cancer Res.,3,2493-500(1997))在有或无所述试验化合物存在下,培养72小时,然后测定掺入到DNA中的[3H]-胸苷的量,作为一种测定细胞数及增殖的方法。将MDA PCa2b细胞系保持在增添10%FBS的BRFF-HPCI培养基(Biological ResearchFaculty & Facility Inc.,MD)中。在该测定中,将细胞放入Biocoated 96-孔微量板中,在37℃下,在10%FBS(活性碳解析)/BRFF-BMZERO(无雄激素)中培养。24小时后,在无(空白)或有1nM DHT(对照)存在下或者用浓度范围为10-10至10-5M的试验化合物(样品)处理该细胞。每个样本采用一式两份进行测定。采用Biomek 2000测定室工作站进行所述化合物的稀释。72小时后,每孔中加入0.44uCi的[3H]-胸苷(Amersham),再培养24小时,接着用胰蛋白酶消化,将细胞收集在GF/B滤膜上。向滤膜中加入Micro-scint PS,然后用Beckman TopCount计数。
%抑制率计算如下:%抑制率=100×(1-[平均值对照-平均值空白/平均值样品-平均值空白])
将数据绘图,定量抑制50%[3H]-胸苷掺入的化合物浓度(IC50)。实施例5:C2C12小鼠成肌细胞反式激活测定
研制两种功能性反式激活测定,采用荧光素酶报道剂测定肌细胞背景的雄激素激动剂效用。第一个测定(ARTA Stable 1)采用细胞系Stable 1(克隆#72),其能稳定表达全长大鼠雄激素受体,但需要瞬时转染增强子/报道剂。该细胞系源于C2C12小鼠成肌细胞。第二个测定(ARTA Stable 2)采用源于Stable 1的细胞系Stable 2(克隆#133),其能稳定表达rAR和增强子/荧光素酶报道剂。这些测定和细胞系
该系统中使用的增强子/报道剂构建物为pGL3/2XDR-1/荧光素酶。据报道2XDR-1是一种CV-1细胞中的AR特异性反应成分,Brown等,The Journal of Biological Chemistry 272,8227-8235,(1997)。其由AR/GR共有增强子序列的随机诱变产生。
为进行ARTA Stable 1测定,以6,000个细胞/孔的量,将Stable 1细胞加入在包含10%活性炭和葡聚糖处理的FBS(HyClone目录号SH30068.02)、50mM HEPES缓冲液(Gibco BRL,目录号15630-080)、1X MEM丙酮酸钠(Gibco BRL,目录号11360-070)、0.5X抗生素-抗霉素和800ug/ml遗传霉素(Gibco BRL,目录号10131-035)的无酚红高葡萄糖DMEM(Gibco BRL,目录号21063-029)中的96孔板中。更详细地讲,将5ng/孔的pGL3/2XDR-1/荧光素酶DNA和50ng/孔的鲑精DNA(作为载体)用5μl/孔Opti-MEMem培养基(Gibco BRL,目录号31985-070)稀释。向其中加入0.5μl/孔Plus试剂。室温下,将该混合物温育15分钟。在另一容器中,将0.385μl/孔的脂质转染胺试剂用5μl/孔的Opti-MEM培养基稀释。然后将该DNA混合物与该脂质转染胺试剂混合物混合,室温下,再温育15分钟。本发明期间,从该细胞中移出培养基,并用60μl/孔的Opti-MEM代替。向其中加入10μl/孔的DNA/脂质转染胺试剂转染混合物。将所述细胞培养4小时。培养后,从细胞中除去转染混合物,用包含10%活性炭和葡聚糖处理的FBS(HyClone目录号SH30068.02)、50mM HEPES缓冲液(Gibco BRL,目录号15630-080)、1X MEM丙酮酸钠(Gibco BRL,目录号11360-070)、0.5X抗生素-抗霉素和800ug/ml遗传霉素(GibcoBRL,目录号10131-035)的无酚红的90ul高葡萄糖DMEM(GibcoBRL,目录号21063-029)代替。然后以适当的药物稀释浓度,向各孔中加入10μl/孔的试验化合物。24小时后,根据商品说明书(Promega,目录号E2520),采用Steady-GloTM荧光素酶测定系统测定活性。
为进行ARTA Stable 2测定,以6,000个细胞/孔,将Stable 2细胞加入在包含10%活性炭和葡聚糖处理的FBS(HyClone目录号SH30068.02)、50mM HEPES缓冲液(Gibco BRL,目录号15630-080)、1X MEM丙酮酸钠(Gibco BRL,目录号11360-070)、0.5X抗生素-抗霉素、800ug/ml遗传霉素(Gibco BRL,目录号10131-035)和800ug/ml潮霉素β(Gibco BRL,目录号10687-010)的无酚红高葡萄糖DMEM(Gibco BRL,目录号21063-029)中的96孔板中。48小时后,除去细胞上的培养基,用90μl新鲜培养基代替。然后以适当的药物稀释浓度,向各孔中加入10μl/孔的试验化合物。24小时后,根据商品说明书(Promega,目录号E2520),采用Steady-GloTM荧光素酶测定系统测定活性。参见Jacek Ostrowski等在2001年6月20日申请的题为“Cell Lines and Cell-Based Assays For Identification of AndrogenReceptor Modulators”的美国专利申请序列号__(未给定)(代理档案号D 0177),该专利申请全文结合到本发明中作为参考。实施例6:小鼠乳腺细胞增殖测定
通过采用源于Shionogi肿瘤的雄激素反应性小鼠乳腺细胞系(Hiraoka等,Cancer Res.,47,6560-6564(1987)),在增殖测定中测试化合物,确定试验化合物调节AR功能的能力。根据Tetuo等最初报道的通法(Cancer Research 25,1168-1175(1965)),通过传代肿瘤碎片,建立Shionogi母系的稳定AR依赖性克隆体。从以上方法中,将一稳定细胞系SC114分离、表征,然后用于测试实施例化合物。在有或无所述试验化合物存在下,将SC114细胞培养72小时,然后测定掺入到DNA中的[3H]-胸苷的量,作为一种测定细胞数及增殖率的替代终点,见Suzuki等的说明(J.Steroid Biochem.Mol.Biol.37,559-567(1990))。将SC114细胞系保持在包含10-8M睾丸素和2%DCC-处理的FCS的MEM中。在该测定中,将细胞放入96-孔微量板中的保持培养基内,在37℃培养。次日,将培养基换为含有(拮抗剂模型)或不含有(激动剂模型)10-8M睾丸素并含有浓度范围为10-10至10-5M的本发明试验化合物的无血清培养基[Ham氏F-12:MEM(1∶1,v/v),含0.1%BSA]。每个样本采用一式两份进行测定。采用Biomek 2000实验室工作站进行所述化合物的稀释。72小时后,每孔中加入0.44uCi的[3H]-胸苷(Amersham),再培养2小时,接着胰蛋白酶消化,将细胞收集在GF/B滤膜上。向滤膜中加入Micro-scint PS,然后用BeckmanTopCount计数。
对于拮抗剂模型,%对照率计算如下:%对照率=100×(1-[平均值样本-平均值空白/平均值对照-平均值空白])
将数据绘图,测定抑制50%[3H]-胸苷掺入的化合物浓度(IC50)。
对于激动剂模型,%对照率为在DHT这种情况下,与天然激素测定的最大效应相比,试验化合物的效用,计算如下:%对照率=100×(平均值样本-平均值空白)/(平均值对照-平均值空白)
将数据绘图,测定抑制50%[3H]-胸苷掺入的化合物浓度(EC50)。实施例7:前列腺湿重测定性AR拮抗剂测定
试验化合物作为拮抗剂的活性可采用未成熟的雄性大鼠模型,对给定化合物的用标准的、公认的抗雄性活性测定进行测定(Hershberger等,Proc.Soc.Expt.Biol.Med.,83,175(1953);Walsh.P.C.和Gittes,R.F.,Endocrinology,86,624(1970);和Furr等,J.Endocrinol.,113,R7-9(1987))。该测定的基础是基于雄性性附属器官,如前列腺和精囊,在生殖功能中起着重要作用的这一事实。血清睾丸素(T)的持续存在可刺激这些腺体生长,并使其保持一定的体积和分泌功能,睾丸素是主要的血清雄激素(>95%),其由睾丸内间质细胞产生,受垂体黄体生成素(LH)和促卵泡激素(FSH)控制。通过5α-还原酶,可在前列腺内将睾丸素转化为活性更高的形式,即二氢睾丸素(DHT)。肾上腺雄激素也占大鼠前列腺内总DHT的约20%,而在65岁男人中其占40%(Labrie等,Clin.Invest.Med.,16,475-492(1993))。但是,这并不是主要的途径,原因是在不同时切除肾上腺情况下,动物和人阉割都导致前列腺和精囊的几乎完全退化。因此,在正常情况下,肾上腺并不支持前列腺组织的显著生长(Luke,M.C.和Coffey,D.S.“The Physiology of Reproduction”E.Knobil和J.D.Neill主编,1,1435-1487(1994))。由于雄性性器官是对雄激素活性调节最敏感的器官,所以采用该模型测定未成熟的阉割大鼠性附属器官的雄激素依赖性生长。
在甲氟乙烷麻醉下,将雄性未成熟大鼠(19-20日龄,Sprague-Dawley,Harlan Sprague-Dawley)阉割。手术5日后,将这些阉割的大鼠(60-70g,23-25日龄)服药3日。采用皮下(s.c.)给药给予动物1mg/kg的睾丸素丙酸酯(TP)的花生油液,将试验化合物(本发明化合物)溶于/混悬于80%PEG400和20%吐温80(PEGTW)中,通过管饲法(p.o.)给予。以每100g体重0.5ml溶媒的量,给动物服用溶媒。测定组别如下:
1.对照溶媒
2.睾丸素丙酸酯(TP)(3mg/大鼠/日,皮下给药)
3.TP+卡索地司(p.o.给予其PEGTW液,QD),卡索地司是一种公认的抗雄性激素剂,它用作参考化合物。
4.为测定拮抗剂活性,在一定剂量范围内,给予试验化合物(p.o.给予其PEGTW液,QD)和TP(第2组s.c.给予)。
5.为测定激动剂活性,在一定剂量范围内,给予试验化合物(p.o.给予其PEGTW液,QD)。
3日治疗后,将动物处死,称量腹前列腺重量。为比较不同测定组别的数据,先将性器官的重量统一为每100g体重的mg数,然后将TP诱发增加的器官重量增加当作最大增加量(100%)。然后采用ANOVA,接着用单侧Student或Fisher准确检验进行统计分析。
依据血清雄激素浓度不同,性器官重量的增减反映细胞数目(DNA含量)和细胞量(蛋白质含量)的变化(Okuda等,J.Urol.,145,188-191(1991))。因此,测定器官的湿重足以表明雄激素和雄激素拮抗剂的生物活性。在未成熟阉割的大鼠中,外源性雄激素的替代能以剂量依赖的方式增加精囊(SV)和腹前列腺(VP)的重量。
当给服3mg/大鼠/日的睾丸素(T)或1mg/大鼠/日的睾丸素丙酸酯(TP)3日时,器官重量最大增加4-5倍。T和TP的EC50分别为1mg和0.03mg。VP和SV重量增加还与血清T和DHT浓度的增加相关。虽然皮下注射2小时后,服用T比服用TP的血清T和DHT浓度高5倍,但是,此后这种高水平非常快速衰退。相反,TP-处理的动物中其血清T和DHT浓度在24小时内非常稳定,因此,TP比游离的T呈现出10-30倍高的效果。
在这种未成熟阉割的大鼠模型中,还可与0.1mg的TP(ED80)一起同时给予已知的AR拮抗剂(卡索地司),以剂量依赖性方式抑制睾丸素介导的VP和SV重量增加。当口服或皮下给予拮抗剂时,其拮抗作用类似。本发明的SARM通过抑制睾丸素介导的VP和SV重量的增加,呈现出AR拮抗剂活性。实施例8:肛提肌&前列腺湿重测定性AR拮抗剂测定
试验化合物作为激动剂的活性,可采用未成熟的雄性大鼠模型,该模型是公认的测定给定化合物的肌肉合成代谢作用及性器官维持作用的方法(Hershberger等,Proc.Soc.Expt.Biol.Med.,83,175(1953);Beyler等,J.Amer.Med.Women’s Ass.,23,708(1968);Fukuda等,Nago Dai.Yak.Ken.Nem.14,84(1966))。该测定的基础是在于雄激素剂药物对动物或男人肌肉组织和性附属器官的维持和生长的明确作用。雄性激素甾体类(如睾丸素(T))的维持肌肉量的能力已充分表征。将阉割后的动物或人用外源性T治疗可使萎缩的肌肉恢复。T对大鼠肛提肌肌萎缩的影响已得到充分证实。(Masuoka等,Am.J.Anat.119,263(1966);Gori等,Boll.-Soc.Ital.Biol.Sper.42,1596(1966);Gori等,Boll.-Soc.Ital.Biol.Sper.42,1600(1966);Boris等,Steroids 15,61(1970))。如实施例6所述,充分说明了雄激素对维持雄性性附属器官(如前列腺和精囊)的作用。阉割导致前列腺和精囊的快速退化和萎缩。该影响可通过外源性加入雄激素恢复。由于肛提肌和雄性性器官都是对雄激素剂作用最敏感的器官,所以采用该模型测定未成熟阉割大鼠的肛提肌肌肉和性附属器官的雄激素依赖性萎缩恢复作用。
从卖主处(Taconic)购得阉割的性成熟大鼠(200-250g,6-8周龄,Sprague-Dawley,Harlan)。将大鼠分组,用以下其中一种方式每日处理7-14日:
1.对照溶媒
2.睾丸素丙酸酯(TP)(3mg/大鼠/日,皮下给药)
3.TP+卡索地司(p.o.给予其PEGTW液,QD),卡索地司是一种公认的抗雄性激素剂,用作参考化合物。
4.为测定拮抗剂活性,在一定剂量范围内,给予试验化合物(p.o.给予其PEGTW液,QD)和TP(第2组给药法为s.c给予)。
5.为测定激动剂活性,在一定剂量范围内,给予试验化合物(p.o.给予其PEGTW液,QD)。
7-14日治疗的最后,将动物用二氧化碳处死,称量肛提肌、精囊和腹前列腺重量。为比较不同测定组别的数据,先将肛提肌和性器官的重量统一为每100g体重的mg数,然后将TP诱发增加的器官重量增加当作最大增加量(100%)。采用Super-anova(单因素)进行统计分析。
依据血清雄激素浓度不同,性器官重量的增减反映细胞数目(DNA含量)和细胞量(蛋白质含量)的变化(Okuda等,J.Urol.,145,188-191(1991))。因此,测定器官的湿重足以表明该雄激素和雄激素拮抗剂的生物活性。在未成熟阉割的大鼠中,外源性雄激素的替代能以剂量依赖的方式增加肛提肌、精囊(SV)和前列腺的重量。
当给服3mg/大鼠/日的睾丸素(T)或1mg/大鼠/日的睾丸素丙酸酯(TP)3日时,器官重量最大增加4-5倍。T和TP的EC50分别为1mg和0.03mg。VP和SV重量的增加还与血清T和DHT浓度的增加相关。虽然皮下注射2小时后,服用T比服用TP的血清T和DHT浓度高5倍,但是此后这种高水平非常快速衰退。相反,TP-处理的动物中其血清T和DHT浓度在24小时内非常稳定,因此,TP比游离的T呈现出10-30倍高的效果。实施例9:成熟大鼠前列腺重量测定
试验化合物的活性还采用成熟雄性大鼠模型测定,该模型是实施例7中说明的肛提肌和前列腺湿重测定的一种变型。实施例6和7的体内测定法是对给定化合物测定其对肌肉的合成代谢作用和对性器官的维持功能作用的公认测定(Hershberger等,Proc.Soc.Expt.Biol.Med.,83,175(1953);Beyler等,J.Amer.Med.Women’s Ass.,23,708(1968);Fukuda等,Nago Dai.Yak.Ken.Nem.14,84(1966))。该测定的基础是在于雄激素药物对动物或男人肌肉组织和性附属器官的维持和生长的明确作用。
雄性性附属器官,如前列腺和精囊,在生殖功能中起着重要作用。血清睾丸素(T)的持续存在可刺激这些腺体生长,并使其保持一定的大小和分泌功能,睾丸素是主要的血清雄激素(>95%),其由睾丸内间质细胞产生,受垂体黄体生成素(LH)和促卵泡激素(FSH)控制。通过5α-还原酶,可在前列腺内将睾丸素转化为活性更高的形式,即二氢睾丸素(DHT)。肾上腺雄激素也占大鼠前列腺总DHT的约20%,而在65岁男人中其占40%(Labrie等,Clin.Invest.Med.,16,475-492(1993))。但是,这并不是主要的途径,原因是在不同时切除肾上腺情况下,动物和人阉割都导致前列腺和精囊的几乎完全退化。因此,在正常情况下,肾上腺并不支持前列腺组织的显著生长(Luke,M.C.和Coffey,D.S.“The Physiology of Reproduction”,E.Knobil和J.D.Neill主编,1,1435-1487(1994))。由于雄性性器官和肛提肌都是对雄激素活性调节的最敏感的器官,所以采用该模型测定成熟大鼠中调节雄激素受体途径的化合物的活性。
除对组织(如前列腺、精囊和肌肉)具有促有丝分裂活性外,睾丸素还可用作其自身生物合成的负调节物。睾丸间质细胞产生睾丸素受脑垂体释放的循环LH水平控制。LH水平本身受下丘脑区产生的LHRH水平控制。血中的睾丸素水平用于抑制LHRH的分泌,从而降低LH水平,最终降低循环睾丸素的水平。通过测定受试验化合物影响的LH血液水平,可测定所述化合物对该内分泌循环的下丘脑轴的激动剂或拮抗剂活性水平。
将相应组的Harlan Sprague-Dawley大鼠(40-42日龄,180-220g)通过管饲法(p.o.)口服给予溶于/混悬于80%PEG400和20%吐温20(PEGTW)中的试验化合物14天。两个对照组,一个组不阉割,一个组阉割,仅口服给予PEGTW溶媒。以每100g体重0.5ml溶媒的量,给动物服用溶媒。测定组别如下:
1.不阉割的完整溶媒组(p.o.,PEGTW,QD)
2.对照溶媒组(p.o.,PEGTW,QD)
3.Biacalutamide(卡索地司,一种公认的抗雄性激素剂,用作参考化合物)或试验化合物,p.o.给予其PEGTW液,QD(一定剂量范围)。
14日治疗后,将动物处死,手术取出腹前列腺、精囊和肛提肌,称重。为比较不同测定组别的数据,先将器官重量统一为每100g体重的mg数,然后用非阉割完整组各器官值的百分数表示。
大鼠的黄体生成素(rLH)用Biotrak[125I]试剂盒(AmershamPharmacia Biotek),按照说明指导定量测定。该测定基于[125I]rLH与血清中存在的LH竞争性结合Amerlex-M颗粒/抗体混悬液。将与血清温育后,随之洗涤后保留的放射性外推成标准曲线,得到ng/ml的读数。
依据血清雄激素浓度不同,性器官和肛提肌重量的增减反映细胞数目(DNA含量)和细胞量(蛋白质含量)的变化(Okuda等,J.Urol.,145,188-191(1991))。因此,测定器官的湿重足以表明该雄激素和雄激素拮抗剂的生物活性。在成熟大鼠测定中,活性激动剂或者无作用或者能增加一种或多种雄激素敏感器官(肛提肌、前列腺、精囊)的重量,对LH分泌或者无作用或者具有抑制作用。具有拮抗剂活性的化合物降低一种或多种雄激素敏感器官(肛提肌、前列腺、精囊)的重量,对LH分泌或者无作用或者具有降低的抑制作用。实施例10:MDA PCa2b人体前列腺异种移植测定
为进行体内抗肿瘤测定,将MDA-Pca-2b人前列腺肿瘤保持在Balb/c nu/nu裸鼠体内。采用供体小鼠内得到的肿瘤碎块,以皮下移植在成年雄性裸鼠(4-6周龄)内方式,繁殖肿瘤。每5-6周传代肿瘤。
为进行体内抗肿瘤效能测定,在测定开始时,将所需数量的需要测定有意义反应的小鼠集中,用13-号套针,给每个动物皮下移植肿瘤碎块(约50mg)。使肿瘤生长至约100-200mg(该范围外的肿瘤除外),将动物平均分成各治疗和对照组。根据具体的体重处理每只小鼠。每日检查治疗动物与治疗相关的毒性/死亡率。将各组动物称重,然后开始治疗(Wt1),随后再进行后一次的给药治疗(Wt2)。体重差(Wt2-Wt1)提供与治疗有关的毒性大小。
通过一周二次用测径器测定肿瘤来确定肿瘤反应,直至肿瘤达到预定的“目标”大小为0.5g。用下式估算肿瘤重量(mg):
肿瘤重量=(长度×宽度2)/2
以肿瘤生长抑制率(%T/C)表示肿瘤反应终点,定义为治疗肿瘤的平均瘤重(T)与对照组的平均瘤重(C)的比值。
为测定肿瘤细胞的死亡,先用下式计算肿瘤体积的倍增时间:TVDT=对照肿瘤达到目标大小的平均时间(日)-
对照肿瘤达到一半目标大小的平均时间(日),然后用下式计算细胞死亡的对数值Log细胞死亡=(T-C)/(3.32×TVDT)
采用Gehan氏通用性Wilcoxon检定,进行数据的统计性评价。实施例11:CWR22人体前列腺异种移植测定
体内抗肿瘤测定还可用保持在Balb/c nu/nu裸鼠内的CWR22人体前列腺肿瘤进行。采用供体小鼠内得到的肿瘤碎块,以皮下移植在成年雄性裸鼠(4-6周龄)内方式,繁殖肿瘤。每5-6周传代肿瘤。
为进行体内抗肿瘤效能测定,在测定开始时,将所需数量的需要测定有意义反应的小鼠集中,用13-号套针,给每个动物皮下移植肿瘤碎块(约50mg)。使肿瘤生长至约100-200mg(该范围外的肿瘤除外),将动物平均分成各治疗和对照组。根据具体的体重处理每只小鼠。每日检查治疗动物与治疗相关的毒性/死亡率。将各组动物称重,然后开始治疗(Wt1),随后再进行后一次的给药治疗(Wt2)。体重差(Wt2-Wt1)提供与治疗有关的毒性大小。
通过一周二次用测径器测定肿瘤来确定肿瘤反应,直至肿瘤达到预定“目标”大小为0.5g。用下式估算肿瘤重量(mg):
肿瘤重量=(长度×宽度2)/2
以肿瘤生长抑制率(%T/C)表示肿瘤反应终点,定义为治疗组肿瘤的平均瘤重(T)与对照组的平均瘤重(C)的比值。
为测定肿瘤细胞的死亡,先用下式计算肿瘤体积的倍增时间:TVDT=对照肿瘤达到目标大小的平均时间(日)-
对照肿瘤达到一半目标大小的平均时间(日),然后用下式计算细胞死亡的对数值:Log细胞死亡=(T-C)/(3.32×TVDT)
采用Gehan氏通用性Wilcoxon检验,进行数据的统计性评价。实施例12:Dunning R3327H大鼠前列腺肿瘤测定
Dunning R3327H前列腺肿瘤是一种自然产生的、完全分化的雄性激素敏感的前列腺腺癌(Smolev等,Cancer Treat Rep.61,273-287(1997))。选择雄激素高依赖性生长并在完整的雄性大鼠中可再现生长的R3327H亚系。因此该模型及该肿瘤的其它亚系广泛用于评价抗雄性激素(如氟他胺和bacilutamide/卡索地司)的体内抗肿瘤活性(Maucher A.和von Angerer,J.Cancer Res.Clin.,Oncol.119,669-674(1993),Furr B.J.A.Euro.URL.18(suppl.3),2-9(1990),Shain S.A.和Huot RI.J.Steriod Biochem.31,711-718(1998))。为进行该测定,将Dunning肿瘤碎块(约4×4mm)皮下移植至成熟雄性Copenhagen大鼠(6-7周龄,Harlan-Sprague Dawley,Indianapolis,MD)的胁腹处。移植后约6周时,将这些带有可测大小(约80-120mm3)的肿瘤的动物随机分到治疗组(8-10只大鼠/组),开始给药。将一组大鼠阉割作为肿瘤生长的阴性对照组。将动物每日给予试验化合物、标准抗雄性激素(如bacilutamide)或溶媒(对照),平均进行10-14周。将试验化合物溶于10%聚乙二醇和0.05%吐温-80的1%羧甲基纤维素溶媒,即PEG/CMC(Sigma,St Louis,MO)。对于各标准品或试验化合物(范围300-3mg/kg),典型测定包括三组三个递增剂量。
溶媒对照组肿瘤体积达到1500-2500mm3。相反地,在观察的14周中,所阉割的动物一般呈现出肿瘤停滞现象。与对照组相比,治疗14周后,口服20mg/kg的bacilutamide或氟他胺的动物肿瘤体积降低40%。通过游标测径尺(Froboz,瑞士)每周测定肿瘤体积,得到垂直尺度的长和宽。用下式测定肿瘤体积(mm3):长×宽×高=体积。采用多ANOVO分析,随后通过单侧非参数Student检验,评估测定组和对照组之间的统计学差异。实施例13:Dunning R3327H大鼠前列腺肿瘤和前列腺湿重测定
按实施例11所述,将Dunning肿瘤碎块(约4×4mm)皮下移植至成熟雄性Copenhagen大鼠(6-7周龄,Harlan-Sprague Dawley,Indianapolis,MD)的胁腹处。移植后约6周时,将这些带有可测体积(约80-120mm3)肿瘤的动物随机分成治疗组(8-10只大鼠/组),开始给药。将一组大鼠阉割作为肿瘤生长的阴性对照组。将动物每日给予试验化合物、标准抗雄性激素(如bacilutamide)或溶媒(对照),平均进行10-14周。将试验化合物溶于10%聚乙二醇和0.05%吐温-80的1%羧甲基纤维素(即PEG/CMC(Sigma,St Louis,MO))的溶媒中。对于各标准品或试验化合物(范围300-3mg/kg),典型测定包括三组三个递增剂量。
溶媒对照组肿瘤体积达到1500-2500mm3。相反地,在观察的14周中,所阉割的动物一般呈现出肿瘤停滞现象。与对照组相比,治疗14周后,口服20mg/kg的bacilutamide或氟他胺的动物肿瘤体积降低40%。通过游标测径尺(Froboz,瑞士)每周测定肿瘤体积,得到垂直尺度的长和宽。用下式测定肿瘤体积(mm3):长×宽×高=体积。采用多ANOVO分析,随后通过单侧非参数Student t检验,评估测定组和对照组之间的统计学差异。
治疗结束时,将动物处死,手术取出腹前列腺、精囊和肛提肌,称重。为比较不同测定组别的数据,先将器官重量统一为每100g体重的mg数,然后用完整组各器官值的百分数表示。
大鼠黄体生成素(rLH)用Biotrak[125I]试剂盒(Amersham PharmaciaBiotek),按照说明指导定量测定。该测定基于[125I]rLH与Amerlex-M颗粒/抗体混悬液结合的血清中存在的LH的竞争性。将与血清温度后,随之洗涤后保留的放射性外推成标准曲线,得到ng/ml的读数。
依据血清雄激素浓度不同,性器官和肛提肌重量的增减反映细胞数目(DNA含量)和细胞量(蛋白质含量)的变化(Okuda等,J.Urol.,145,188-191(1991))。因此,测定器官的湿重足以表明雄激素和雄激素拮抗剂的生物活性。在该大鼠测定中,活性激动剂或者无作用或者能增加一种或多种雄激素敏感器官(肛提肌、前列腺、精囊)的重量,对LH分泌或者无作用或者具有抑制作用。具有拮抗剂活性的化合物能降低一种或多种雄激素敏感器官(肛提肌、前列腺、精囊)的重量,对LH分泌或者无作用或者具有降低的抑制作用。
表AATOM 1 CB ILE 672 15.585 25.993 23.410 1.00 31.24ATOM 2 CG2 ILE 672 14.852 27.128 24.154 1.00 30.88ATOM 3 CG1 ILE 672 16.008 24.898 24.385 1.00 31.15ATOM 4 CD1 ILE 672 16.804 25.398 25.547 1.00 31.82ATOM 5 C ILE 672 15.338 24.127 21.758 1.00 30.41ATOM 6 O ILE 672 16.366 24.192 21.075 1.00 30.37ATOM 7 N ILE 672 13.327 25.032 22.857 1.00 31.02ATOM 8 CA ILE 672 14.670 25.387 22.310 1.00 30.84ATOM 9 N PHE 673 14.730 22.987 22.058 1.00 29.49ATOM 10 CA PHE 673 15.233 21.694 21.628 1.00 28.89ATOM 11 CB PHE 673 14.309 20.587 22.143 1.00 28.59ATOM 12 CG PHE 673 14.827 19.211 21.890 1.00 28.37ATOM 13 CD1 PHE 673 15.903 18.721 22.616 1.00 28.33ATOM 14 CD2 PHE 673 14.259 18.412 20.900 1.00 27.95ATOM 15 CE1 PHE 673 16.411 17.447 22.358 1.00 28.35ATOM 16 CE2 PHE 673 14.753 17.151 20.634 1.00 27.76ATOM 17 CZ PHE 673 15.831 16.665 21.361 1.00 28.28ATOM 18 C PHE 673 15.368 21.591 20.108 1.00 28.44ATOM 19 O PHE 673 16.387 21.137 19.594 1.00 28.30ATOM 20 N LEU 674 14.334 22.000 19.387 1.00 28.13ATOM 21 CA LEU 674 14.393 21.950 17.940 1.00 27.74ATOM 22 CB LEU 674 13.033 22.315 17.337 1.00 28.50ATOM. 23 CG LEU 674 12.094 21.110 17.212 1.00 29.52ATOM 24 CD1 LEU 674 12.732 20.084 16.273 1.00 29.84ATOM 25 CD2 LEU 674 11.846 20.487 18.590 1.00 29.46ATOM 26 C LEU 674 15.472 22.876 17.402 1.00 27.02ATOM 27 O LEU 674 16.174 22.529 16.452 1.00 26.73ATOM 28 N ASN 675 15.605 24.048 18.017 1.00 26.63ATOM 29 CA ASN 675 16.595 25.031 17.592 1.00 26.23ATOM 30 CB ASN 675 16.584 26.238 18.547 1.00 26.53ATOM 31 CG ASN 675 15.229 26.955 18.575 1.00 26.69ATOM 32 OD1 ASN 675 14.771 27.475 17.568 1.00 25.27ATOM 33 ND2 ASN 675 14.587 26.973 19.740 1.00 28.17ATOM 34 C ASN 675 17.971 24.371 17.578 1.00 25.92ATOM 35 O ASN 675 18.716 24.475 16.599 1.00 25.60ATOM 36 N VAL 676 18.284 23.666 18.663 1.00 25.22ATOM 37 CA VAL 676 19.561 22.979 18.800 1.00 24.86ATOM 38 CB VAL 676 19.667 22.306 20.180 1.00 24.40ATOM 39 CG1 VAL 676 20.987 21.567 20.300 1.00 23.97ATOM 40 CG2 VAL 676 19.525 23.354 21.271 1.00 24.34ATOM 41 C VAL 676 19.777 21.920 17.715 1.00 24.78ATOM 42 O VAL 676 20.857 21.835 17.123 1.00 23.74ATOM 43 N LEU 677 18.742 21.115 17.471 1.00 24.81ATOM 44 CA LEU 677 18.804 20.055 16.471 1.00 25.01ATOM 45 CB LEU 677 17.540 19.181 16.561 1.00 24.69ATOM 46 CG LEU 677 17.645 17.937 17.468 1.00 25.09ATOM 47 CD1 LEU 677 18.155 18.298 18.847 1.00 24.53ATOM 48 CD2 LEU 677 16.287 17.270 17.570 1.00 24.88ATOM 49 C LEU 677 19.018 20.560 15.037 1.00 24.85ATOM 50 O LEU 677 19.770 19.967 14.274 1.00 24.74ATOM 51 N GLU 678 18.362 21.655 14.675 1.00 25.51ATOM 52 CA GLU 678 18.504 22.232 13.334 1.00 25.67ATOM 53 CB GLU 678 17.413 23.284 13.103 1.00 27.59ATOM 54 CG GLU 678 17.732 24.340 12.046 1.00 30.04ATOM 55 CD GLU 678 16.621 25.379 11.918 1.00 32.44ATOM 56 OE1 GLU 678 16.830 26.423 11.237 1.00 33.09ATOM 57 OE2 GLU 678 15.534 25.140 12.505 1.00 33.23ATOM 58 C GLU 678 19.874 22.873 13.187 1.00 24.83ATOM 59 O GLU 678 20.541 22.715 12.171 1.00 24.31ATOM 60 N ALA 679 20.286 23.591 14.224 1.00 24.77ATOM 61 CA ALA 679 21.571 24.273 14.244 1.00 24.70ATOM 62 CB ALA 679 21.703 25.072 15.515 1.00 24.21ATOM 63 C ALA 679 22.744 23.315 14.125 1.00 25.17ATOM 64 O ALA 679 23.752 23.637 13.499 1.00 25.65ATOM 65 N ILE 680 22.623 22.137 14.722 1.00 25.38ATOM 66 CA ILE 680 23.716 21.172 14.676 1.00 25.89ATOM 67 CB ILE 680 23.829 20.417 15.999 1.00 25.44ATOM 68 CG2 ILE 680 23.886 21.427 17.143 1.00 24.98ATOM 69 CG1 ILE 680 22.649 19.439 16.135 1.00 24.49ATOM 70 CD1 ILE 680 22.583 18.702 17.442 1.00 24.31ATOM 71 C ILE 680 23.620 20.140 13.563 1.00 26.38ATOM 72 O ILE 680 24.482 19.270 13.472 1.00 26.49ATOM 73 N GLU 681 22.586 20.227 12.728 1.00 26.84ATOM 74 CA GLU 681 22.414 19.262 11.641 1.00 28.06ATOM 75 CB GLU 681 21.074 19.473 10.946 1.00 28.71ATOM 76 CG GLU 681 20.790 18.472 9.850 1.00 29.82ATOM 77 CD GLU 681 20.527 17.083 10.393 1.00 31.25ATOM 78 OE1 GLU 681 20.168 16.187 9.588 1.00 32.01ATOM 79 OE2 GLU 681 20.677 16.887 11.623 1.00 31.32ATOM 80 C GLU 681 23.533 19.348 10.605 1.00 28.62ATOM 81 O GLU 681 23.755 20.398 9.993 1.00 29.09ATOM 82 N PRO 682 24.247 18.235 10.384 1.00 28.78ATOM 83 CD PRO 682 24.071 16.919 11.017 1.00 28.67ATOM 84 CA PRO 682 25.348 18.198 9.420 1.O0 28.68ATOM 85 CB PRO 682 25.864 16.764 9.533 1.00 28.60ATOM 86 CG PRO 682 25.440 16.337 10.882 1.00 28.67ATOM 87 C PRO 682 24.886 18.505 8.004 1.00 28.93ATOM 88 O PRO 682 23.765 18.165 7.620 1.00 29.17ATOM 89 N GLY 683 25.760 19.141 7.233 1.00 28.83ATOM 90 CA GLY 683 25.438 19.454 5.855 1.00 28.82ATOM 91 C GLY 683 25.843 18.296 4.951 1.00 29.01ATOM 92 O GLY 683 26.077 17.187 5.421 1.00 28.29ATOM 93 N VAL 684 25.935 18.569 3.652 1.00 29.33ATOM 94 CA VAL 684 26.293 17.569 2.648 1.00 29.92ATOM 95 CB VAL 684 26.276 18.182 1.223 1.00 30.47ATOM 96 CG1 VAL 684 26.393 17.069 0.166 1.00 30.24ATOM 97 CG2 VAL 684 25.004 19.006 1.025 1.00 29.99ATOM 98 C VAL 684 27.666 16.933 2.855 1.00 29.77ATOM 99 O VAL 684 28.602 17.578 3.308 1.00 29.87ATOM 100 N VAL 685 27.768 15.657 2.512 1.00 29.69ATOM 101 CA VAL 685 29.014 14.922 2.631 1.00 29.84ATOM 102 CB VAL 685 28.973 13.936 3.834 1.00 29.89ATOM 103 CG1 VAL 685 30.357 13.368 4.084 1.00 29.18ATOM 104 CG2 VAL 685 28.441 14.642 5.088 1.00 29.80ATOM 105 C VAL 685 29.207 14.130 1.333 1.00 30.42ATOM 106 O VAL 685 28.378 13.291 0.975 1.00 30.40ATOM 107 N CYS 686 30.287 14.408 0.615 1.00 30.75ATOM 108 CA CYS 686 30.551 13.698 -0.624 1.00 31.29ATOM 109 CB CYS 686 31.219 14.636 -1.630 1.00 31.47ATOM 110 SG CYS 686 30.172 16.063 -2.105 1.00 33.49ATOM 111 C CYS 686 31.415 12.459 -0.366 1.00 31.56ATOM 112 O CYS 686 32.266 12.458 0.523 1.00 31.13ATOM 113 N ALA 687 31.180 11.405 -1.147 1.00 31.88ATOM 114 CA ALA 687 31.905 10.157 -0.987 1.00 32.66ATOM 115 CB ALA 687 31.072 8.989 -1.531 1.00 32.89ATOM 116 C ALA 687 33.275 10.160 -1.636 1.00 33.22ATOM 117 O ALA 687 34.138 9.365 -1.259 1.00 33.23ATOM 118 N GLY 688 33.476 11.051 -2.602 1.00 33.83ATOM 119 CA GLY 688 34.752 11.123 -3.287 1.00 34.36ATOM 120 C GLY 688 34.838 10.039 -4.345 1.00 35.22ATOM 121 O GLY 688 35.925 9.648 -4.776 1.00 35.29ATOM 122 N HIS 689 33.681 9.540 -4.762 1.00 35.46ATOM 123 CA HIS 689 33.639 8.497 -5.773 1.00 36.39ATOM 124 CB HIS 689 32.328 7.713 -5.650 1.00 36.01ATOM 125 CG HIS 689 32.136 6.683 -6.716 1.00 35.72ATOM 126 CD2 HIS 689 32.433 5.361 -6.742 1.00 35.47ATOM 127 ND1 HIS 689 31.590 6.977 -7.946 1.00 35.68ATOM 128 CE1 HIS 689 31.557 5.882 -8.684 1.00 35.61ATOM 129 NE2 HIS 689 32.063 4.887 -7.976 1.00 35.45ATOM 130 C HIS 689 33.776 9.088 -7.176 1.00 37.25ATOM 131 O HIS 689 33.125 10.078 -7.512 1.00 36.54ATOM 132 N ASP 690 34.643 8.492 -7.988 1.00 38.49ATOM 133 CA ASP 690 34.832 8.967 -9.353 1.00 40.16ATOM 134 CB ASP 690 36.285 8.755 -9.803 1.00 40.96ATOM 135 CG ASP 690 36.766 7.342 -9.580 1.00 42.31ATOM 136 OD1 ASP 690 37.918 7.030 -9.977 1.00 42.84ATOM 137 OD2 ASP 690 35.994 6.541 -9.004 1.00 43.23ATOM 138 C ASP 690 33.870 8.242 -10.293 1.00 40.81ATOM 139 O ASP 690 33.928 7.020 -10.434 1.00 41.00ATOM 140 N ASN 691 32.972 8.997 -10.919 1.00 41.55ATOM 141 CA ASN 691 31.992 8.419 -11.838 1.00 42.66ATOM 142 CB ASN 691 30.917 9.450 -12.195 1.00 42.57ATOM 143 CG ASN 691 30.002 9.782 -11.031 1.00 42.88ATOM 144 OD1 ASN 691 29.206 10.721 -11.115 1.00 43.45ATOM 145 ND2 ASN 691 30.096 9.014 -9.946 1.00 42.16ATOM 146 C ASN 691 32.620 7.894 -13.132 1.00 43.34ATOM 147 O ASN 691 31.931 7.304 -13.962 1.00 43.67ATOM 148 N ASN 692 33.918 8.120 -13.307 1.00 43.99ATOM 149 CA ASN 692 34.626 7.661 -14.499 1.00 44.50ATOM 150 CB ASN 692 36.045 8.233 -14.521 1.00 44.96ATOM 151 CG ASN 692 36.163 9.552 -13.757 1.00 45.75ATOM 152 OD1 ASN 692 35.869 9.625 -12.558 1.00 45.86ATOM 153 ND2 ASN 692 36.604 10.598 -14.449 1.00 45.86ATOM 154 C ASN 692 34.703 6.138 -14.431 1.00 44.51ATOM 155 O ASN 692 35.016 5.467 -15.415 1.00 44.65ATOM 156 N GLN 693 34.401 5.620 -13.247 1.00 44.30ATOM 157 CA GLN 693 34.432 4.195 -12.933 1.00 44.20ATOM 158 CB GLN 693 34.091 4.004 -11.452 1.00 44.34ATOM 159 CG GLN 693 34.453 2.664 -10.864 1.00 44.63ATOM 160 CD GLN 693 35.935 2.552 -10.548 1.00 44.93ATOM 161 OE1 GLN 693 36.544 3.501 -10.055 1.00 44.97ATOM 162 NE2 GLN 693 36.518 1.383 -10.813 1.00 44.61ATOM 163 C GLN 693 33.469 3.362 -13.765 1.00 43.84ATOM 164 O GLN 693 32.271 3.634 -13.802 1.00 44.50ATOM 165 N PRO 694 33.976 2.324 -14.439 1.00 43.36ATOM 166 CD PRO 694 35.372 1.893 -14.620 1.00 43.36ATOM 167 CA PRO 694 33.069 1.503 -15.238 1.00 43.02ATOM 168 CB PRO 694 34.021 0.607 -16.027 1.00 43.07ATOM 169 CG PRO 694 35.200 0.484 -15.122 1.00 43.30ATOM 170 C PRO 694 32.111 0.717 -14.338 1.00 42.75ATOM 171 O PRO 694 31.333 -0.121 -14.816 1.00 43.47ATOM 172 N ASP 695 32.174 0.993 -13.036 1.00 41.47ATOM 173 CA ASP 695 31.309 0.342 -12.056 1.00 40.30ATOM 174 CB ASP 695 29.858 0.406 -12.521 1.00 40.36ATOM 175 CG ASP 695 28.998 1.238 -11.610 1.00 40.64ATOM 176 OD1 ASP 695 27.988 1.793 -12.085 1.00 40.36ATOM 177 OD2 ASP 695 29.329 1.329 -10.411 1.00 41.36ATOM 178 C ASP 695 31.701 -1.103 -11.772 1.00 39.59ATOM 179 O ASP 695 32.158 -1.829 -12.661 1.00 39.66ATOM 180 N SER 696 31.519 -1.511 -10.523 1.00 37.97ATOM 181 CA SER 696 31.870 -2.854 -10.093 1.00 36.83ATOM 182 CB SER 696 33.334 -3.141 -10.409 1.00 36.85ATOM 183 OG SER 696 34.170 -2.172 -9.803 1.00 36.78ATOM 184 C SER 696 31.658 -2.985 -8.595 1.00 35.83ATOM 185 O SER 696 31.175 -2.063 -7.938 1.00 35.84ATOM 186 N PHE 697 32.034 -4.135 -8.058 1.00 34.43ATOM 187 CA PHE 697 31.886 -4.376 -6.639 1.00 33.31ATOM 188 CB PHE 697 31.970 -5.872 -6.353 1.00 32.81ATOM 189 CG PHE 697 31.755 -6.225 -4.910 1.00 32.02ATOM 190 CD1 PHE 697 30.601 -5.839 -4.253 1.00 31.59ATOM 191 CD2 PHE 697 32.712 -6.939 -4.207 1.00 31.69ATOM 192 CE1 PHE 697 30.411 -6.162 -2.913 1.00 31.45ATOM 193 CE2 PHE 697 32.522 -7.264 -2.871 1.00 31.30ATOM 194 CZ PHE 697 31.375 -6.875 -2.227 1.00 30.74ATOM 195 C PHE 697 32.959 -3.634 -5.849 1.00 32.77ATOM 196 O PHE 697 32.663 -2.997 -4.846 1.00 32.24ATOM 197 N ALA 698 34.199 -3.701 -6.326 1.00 32.43ATOM 198 CA ALA 698 35.333 -3.059 -5.659 1.00 32.06ATOM 199 CB ALA 698 36.628 -3.462 -6.351 1.00 32.14ATOM 200 C ALA 698 35.252 -1.533 -5.562 1.00 31.78ATOM 201 O ALA 698 35.503 -0.958 -4.506 1.00 31.59ATOM 202 N ALA 699 34.903 -0.883 -6.663 1.00 31.20ATOM 203 CA ALA 699 34.799 0.569 -6.692 1.00 30.50ATOM 204 CB ALA 699 34.627 1.035 -8.125 1.00 30.71ATOM 205 C ALA 699 33.658 1.117 -5.837 1.00 30.14ATOM 206 O ALA 699 33.793 2.161 -5.192 1.00 29.89ATOM 207 N LEU 700 32.525 0.425 -5.856 1.00 29.56ATOM 208 CA LEU 700 31.353 0.846 -5.092 1.00 29.08ATOM 209 CB LEU 700 30.166 -0.054 -5.431 1.00 29.19ATOM 210 CG LEU 700 29.075 0.521 -6.332 1.00 30.19ATOM 211 CD1 LEU 700 29.649 1.531 -7.321 1.00 29.81ATOM 212 CD2 LEU 700 28.377 -0.636 -7.053 1.00 30.55ATOM 213 C LEU 700 31.600 0.817 -3.587 1.00 28.70ATOM 214 O LEU 700 31.687 1.858 -2.939 1.00 28.63ATOM 215 N LEU 701 31.718 -0.387 -3.045 1.00 28.11ATOM 216 CA LEU 701 31.944 -0.580 -1.624 1.00 28.02ATOM 217 CB LEU 701 32.126 -2.068 -1.325 1.00 26.80ATOM 218 CG LEU 701 30.785 -2.788 -1.243 1.00 26.52ATOM 219 CD1 LEU 701 29.977 -2.199 -0.085 1.00 25.48ATOM 220 CD2 LEU 701 30.028 -2.659 -2.562 1.00 25.47ATOM 221 C LEU 701 33.126 0.200 -1.079 1.00 28.03ATOM 222 O LEU 701 33.065 0.744 0.023 1.00 27.83ATOM 223 N SER 702 34.200 0.250 -1.857 1.00 28.39ATOM 224 CA SER 702 35.397 0.965 -1.446 1.00 28.48ATOM 225 CB SER 702 36.508 0.793 -2.478 1.00 28.93ATOM 226 OG SER 702 37.745 1.184 -1.922 1.00 30.72ATOM 227 C SER 702 35.078 2.440 -1.266 1.00 27.81ATOM 228 O SER 702 35.585 3.072 -0.345 1.00 29.06ATOM 229 N SER 703 34.233 2.984 -2.140 1.00 27.29ATOM 230 CA SER 703 33.850 4.388 -2.040 1.00 26.12ATOM 231 CB SER 703 33.349 4.916 -3.385 1.00 26.33ATOM 232 OG SER 703 31.941 5.056 -3.376 1.00 28.04ATOM 233 C SER 703 32.762 4.510 -0.981 1.00 25.38ATOM 234 O SER 703 32.637 5.543 -0.333 1.00 25.43ATOM 235 N LEU 704 31.975 3.453 -0.791 1.00 24.62ATOM 236 CA LEU 704 30.945 3.492 0.247 1.00 23.83ATOM 237 CB LEU 704 29.987 2.306 0.122 1.00 23.34ATOM 238 CG LEU 704 28.843 2.445 -0.888 1.00 22.81ATOM 239 CD1 LEU 704 27.962 1.199 -0.844 1.00 22.05ATOM 240 CD2 LEU 704 28.010 3.673 -0.530 1.00 22.63ATOM 241 C LEU 704 31.629 3.473 1.614 1.00 23.67ATOM 242 O LEU 704 31.212 4.171 2.537 1.00 23.27ATOM 243 N ASN 705 32.681 2.663 1.728 1.00 23.68ATOM 244 CA ASN 705 33.454 2.556 2.959 1.00 23.54ATOM 245 CB ASN 705 34.597 1.546 2.808 1.00 22.57ATOM 246 CG ASN 705 34.135 0.107 2.920 1.00 22.79ATOM 247 OD1 ASN 705 34.865 -0.826 2.553 1.00 22.63ATOM 248 ND2 ASN 705 32.932 -0.089 3.447 1.00 21.75ATOM 249 C ASN 705 34.051 3.920 3.248 1.00 23.95ATOM 250 O ASN 705 34.095 4.355 4.395 1.00 24.17ATOM 251 N GLU 706 34.513 4.599 2.204 1.00 24.44ATOM 252 CA GLU 706 35.110 5.907 2.402 1.00 25.29ATOM 253 CB GLU 706 35.729 6.452 1.118 1.00 26.16ATOM 254 CG GLU 706 36.404 7.788 1.340 1.00 27.89ATOM 255 CD GLU 706 37.478 7.726 2.428 1.00 29.25ATOM 256 OE1 GLU 706 37.936 8.799 2.881 1.00 29.77ATOM 257 OE2 GLU 706 37.868 6.604 2.831 1.00 30.55ATOM 258 C GLU 706 34.063 6.874 2.884 1.00 25.01ATOM 259 O GLU 706 34.352 7.747 3.694 1.00 25.76ATOM 260 N LEU 707 32.842 6.714 2.385 1.00 24.51ATOM 261 CA LEU 707 31.749 7.585 2.778 1.00 24.01ATOM 262 CB LEU 707 30.511 7.333 1.912 1.00 23.04ATOM 263 CG LEU 707 29.345 8.281 2.195 1.00 22.39ATOM 264 CD1 LEU 707 29.746 9.740 1.906 1.00 21.36ATOM 265 CD2 LEU 707 28.168 7.883 1.343 1.00 22.62ATOM 266 C LEU 707 31.382 7.379 4.230 1.00 24.28ATOM 267 O LEU 707 31.075 8.333 4.941 1.00 24.68ATOM 268 N GLY 708 31.414 6.126 4.666 1.00 24.48ATOM 269 CA GLY 708 31.052 5.818 6.033 1.00 24.27ATOM 270 C GLY 708 31.987 6.483 7.013 1.00 24.28ATOM 271 O GLY 708 31.557 6.976 8.043 1.00 24.53ATOM 272 N GLU 709 33.271 6.488 6.688 1.00 24.50ATOM 273 CA GLU 709 34.278 7.094 7.548 1.00 25.04ATOM 274 CB GLU 709 35.676 6.727 7.037 1.00 26.02ATOM 275 CG GLU 709 36.846 7.291 7.830 1.00 28.27ATOM 276 CD GLU 709 36.963 6.712 9.238 1.00 30.06ATOM 277 OE1 GLU 709 36.142 7.085 10.116 1.00 30.97ATOM 278 OE2 GLU 709 37.882 5.884 9.466 1.00 30.27ATOM 279 C GLU 709 34.083 8.613 7.571 1.00 24.49ATOM 280 O GLU 709 34.176 9.240 8.624 1.00 24.26ATOM 281 N ARG 710 33.792 9.198 6.414 1.00 23.72ATOM 282 CA ARG 710 33.581 10.639 6.342 1.00 23.54ATOM 283 CB ARG 710 33.426 11.097 4.885 1.00 23.22ATOM 284 CG ARG 710 34.715 10.999 4.073 1.00 23.82ATOM 285 CD ARG 710 34.524 11.398 2.626 1.00 24.53ATOM 286 NE ARG 710 35.807 11.550 1.952 1.00 25.26ATOM 287 CZ ARG 710 35.967 12.064 0.737 1.00 25.57ATOM 288 NH1 ARG 710 34.920 12.481 0.036 1.00 25.76ATOM 289 NH2 ARG 710 37.183 12.180 0.226 1.00 26.08ATOM 290 C ARG 710 32.365 11.065 7.152 1.00 23.53ATOM 291 O ARG 710 32.404 12.074 7.867 1.00 23.75ATOM 292 N GLN 711 31.286 10.294 7.052 1.00 23.34ATOM 293 CA GLN 711 30.081 10.627 7.786 1.00 23.12ATOM 294 CB GLN 711 28.893 9.819 7.274 1.00 22.95ATOM 295 CG GLN 711 28.250 10.414 6.037 1.00 22.79ATOM 296 CD GLN 711 26.952 9.724 5.655 1.00 23.04ATOM 297 OE1 GLN 711 26.165 9.329 6.519 1.00 23.05ATOM 298 NE2 GLN 711 26.715 9.587 4.356 1.00 22.64ATOM 299 C GLN 711 30.285 10.400 9.273 1.00 23.07ATOM 300 O GLN 711 29.672 11.072 10.092 1.00 22.74ATOM 301 N LEU 712 31.159 9.458 9.617 1.00 23.12ATOM 302 CA LEU 712 31.459 9.179 11.018 1.00 22.87ATOM 303 CB LEU 712 32.475 8.046 11.131 1.00 22.35ATOM 304 CG LEU 712 33.072 7.933 12.536 1.00 22.63ATOM 305 CD1 LEU 712 31.940 7.890 13.580 1.00 22.01ATOM 306 CD2 LEU 712 33.969 6.701 12.615 1.00 22.12ATOM 307 C LEU 712 32.029 10.452 11.651 1.00 23.01ATOM 308 O LEU 712 31.681 10.822 12.784 1.00 22.93ATOM 309 N VAL 713 32.907 11.119 10.907 1.00 22.87ATOM 310 CA VAL 713 33.498 12.362 11.374 1.00 22.95ATOM 311 CB VAL 713 34.344 13.042 10.255 1.00 23.84ATOM 312 CG1 VAL 713 34.691 14.487 10.648 1.00 22.62ATOM 313 CG2 VAL 713 35.613 12.226 9.988 1.00 23.07ATOM 314 C VAL 713 32.384 13.319 11.796 1.00 22.67ATOM 315 O VAL 713 32.475 13.957 12.847 1.00 22.99ATOM 316 N HIS 714 31.333 13.404 10.981 1.00 22.28ATOM 317 CA HIS 714 30.211 14.302 11.266 1.00 22.20ATOM 318 CB HIS 714 29.444 14.647 9.980 1.00 22.70ATOM 319 CG HIS 714 30.235 15.456 9.001 1.00 22.67ATOM 320 CD2 HIS 714 30.626 16.751 9.026 1.00 22.73ATOM 321 ND1 HIS 714 30.735 14.928 7.830 1.00 23.24ATOM 322 CE1 HIS 714 31.401 15.863 7.175 1.00 22.99ATOM 323 NE2 HIS 714 31.350 16.979 7.880 1.00 23.40ATOM 324 C HIS 714 29.215 13.816 12.310 1.00 21.81ATOM 325 O HIS 714 28.598 14.627 12.994 1.00 22.68ATOM 326 N VAL 715 29.031 12.509 12.429 1.00 21.29ATOM 327 CA VAL 715 28.099 11.992 13.423 1.00 20.49ATOM 328 CB VAL 715 27.785 10.476 13.188 1.00 20.64ATOM 329 CG1 VAL 715 27.000 9.897 14.361 1.00 20.52ATOM 330 CG2 VAL 715 26.960 10.318 11.921 1.00 19.86ATOM 331 C VAL 715 28.697 12.211 14.808 1.00 20.28ATOM 332 O VAL 715 27.975 12.476 15.759 1.00 20.31ATOM 333 N VAL 716 30.020 12.119 14.917 1.00 19.96ATOM 334 CA VAL 716 30.680 12.331 16.203 1.00 19.21ATOM 335 CB VAL 716 32.214 12.047 16.125 1.00 18.74ATOM 336 CG1 VAL 716 32.889 12.440 17.427 1.00 17.72ATOM 337 CG2 VAL 716 32.457 10.566 15.849 1.00 18.72ATOM 338 C VAL 716 30.463 13.766 16.693 1.00 19.14ATOM 339 O VAL 716 30.008 13.976 17.806 1.00 19.96ATOM 340 N LYS 717 30.788 14.748 15.865 1.00 18.52ATOM 341 CA LYS 717 30.620 16.139 16.256 1.00 18.43ATOM 342 CB LYS 717 31.233 17.074 15.181 1.00 19.20ATOM 343 CG LYS 717 32.760 17.074 15.191 1.00 20.49ATOM 344 CD LYS 717 33.397 17.385 13.835 1.00 22.01ATOM 345 CE LYS 717 33.242 18.841 13.423 1.00 23.42ATOM 346 NZ LYS 717 34.179 19.195 12.301 1.00 23.88ATOM 347 C LYS 717 29.149 16.462 16.484 1.00 17.83ATOM 348 O LYS 717 28.809 17.280 17.330 1.00 18.37ATOM 349 N TRP 718 28.276 15.806 15.733 1.00 17.26ATOM 350 CA TRP 718 26.844 16.032 15.863 1.00 16.62ATOM 351 CB TRP 718 26.096 15.283 14.747 1.00 15.39ATOM 352 CG TRP 718 24.636 15.139 14.991 1.00 13.87ATOM 353 CD2 TRP 718 23.955 13.949 15.416 1.00 13.60ATOM 354 CE2 TRP 718 22.583 14.272 15.530 1.00 13.27ATOM 355 CE3 TRP 718 24.373 12.639 15.710 1.00 12.87ATOM 356 CD1 TRP 718 23.683 16.105 14.871 1.00 13.87ATOM 357 NE1 TRP 718 22.444 15.594 15.191 1.00 13.38ATOM 358 CZ2 TRP 718 21.622 13.334 15.929 1.00 12.65ATOM 359 CZ3 TRP 718 23.417 11.705 16.106 1.00 12.99ATOM 360 CH2 TRP 718 22.054 12.060 16.212 1.00 12.90ATOM 361 C TRP 718 26.378 15.565 17.243 1.00 16.98ATOM 362 O TRP 718 25.760 16.319 18.012 1.00 15.96ATOM 363 N ALA 719 26.692 14.312 17.549 1.00 17.83ATOM 364 CA ALA 719 26.326 13.721 18.819 1.00 18.17ATOM 365 CB ALA 719 26.835 12.287 18.887 1.00 18.35ATOM 366 C ALA 719 26.891 14.534 19.978 1.00 18.72ATOM 367 O ALA 719 26.148 14.907 20.886 1.00 18.90ATOM 368 N LYS 720 28.195 14.822 19.933 1.00 19.47ATOM 369 CA LYS 720 28.870 15.570 21.003 1.00 20.52ATOM 370 CB LYS 720 30.358 15.793 20.663 1.00 21.24ATOM 371 CG LYS 720 31.257 14.541 20.709 1.00 21.82ATOM 372 CD LYS 720 31.657 14.170 22.135 1.00 22.50ATOM 373 CE LYS 720 32.458 12.850 22.217 1.00 23.14ATOM 374 NZ LYS 720 33.777 12.847 21.507 1.00 22.87ATOM 375 C LYS 720 28.215 16.912 21.316 1.00 20.70ATOM 376 O LYS 720 28.338 17.418 22.429 1.00 21.08ATOM 377 N ALA 721 27.520 17.487 20.338 1.00 20.77ATOM 378 CA ALA 721 26.844 18.760 20.549 1.00 20.21ATOM 379 CB ALA 721 26.944 19.614 19.300 1.00 20.14ATOM 380 C ALA 721 25.378 18.592 20.944 1.00 20.23ATOM 381 O ALA 721 24.664 19.582 21.088 1.00 20.39ATOM 382 N LEU 722 24.925 17.352 21.116 1.00 20.40ATOM 383 CA LEU 722 23.536 17.103 21.497 1.00 21.36ATOM 384 CB LEU 722 23.166 15.627 21.282 1.00 21.25ATOM 385 CG LEU 722 22.682 15.273 19.866 1.00 21.90ATOM 386 CD1 LEU 722 22.656 13.756 19.658 1.00 20.78ATOM 387 CD2 LEU 722 21.312 15.893 19.632 1.00 21.16ATOM 388 C LEU 722 23.228 17.497 22.944 1.00 22.09ATOM 389 O LEU 722 24.085 17.429 23.826 1.00 22.42ATOM 390 N PRO 723 21.996 17.941 23.202 1.00 22.76ATOM 391 CD PRO 723 20.936 18.384 22.273 1.00 22.83ATOM 392 CA PRO 723 21.688 18.318 24.586 1.00 23.30ATOM 393 CB PRO 723 20.256 18.860 24.490 1.00 23.27ATOM 394 CG PRO 723 20.207 19.447 23.086 1.00 22.63ATOM 395 C PRO 723 21.787 17.131 25.539 1.00 23.84ATOM 396 O PRO 723 21.100 16.132 25.360 1.00 23.75ATOM 397 N GLY 724 22.658 17.236 26.537 1.00 24.31ATOM 398 CA GLY 724 22.788 16.172 27.524 1.00 24.68ATOM 399 C GLY 724 23.653 14.966 27.180 1.00 25.55ATOM 400 O GLY 724 23.896 14.114 28.040 1.00 25.10ATOM 401 N PHE 725 24.113 14.876 25.935 1.00 25.87ATOM 402 CA PHE 725 24.950 13.757 25.535 1.00 26.37ATOM 403 CB PHE 725 25.373 13.898 24.077 1.00 25.67ATOM 404 CG PHE 725 26.116 12.706 23.560 1.00 25.20ATOM 405 CD1 PHE 725 25.428 11.572 23.140 1.00 24.92ATOM 406 CD2 PHE 725 27.505 12.689 23.546 1.00 24.47ATOM 407 CE1 PHE 725 26.117 10.429 22.712 1.00 24.76ATOM 408 CE2 PHE 725 28.198 11.554 23.121 1.00 24.71ATOM 409 CZ PHE 725 27.498 10.422 22.704 1.00 24.40ATOM 410 C PHE 725 26.202 13.693 26.412 1.00 27.46ATOM 411 O PHE 725 26.593 12.622 26.880 1.00 27.31ATOM 412 N ARG 726 26.830 14.851 26.618 1.00 28.62ATOM 413 CA ARG 726 28.039 14.951 27.430 1.00 29.72ATOM 414 CB ARG 726 28.557 16.389 27.416 1.00 30.89ATOM 415 CG ARG 726 29.272 16.781 26.134 1.00 32.52ATOM 416 CD ARG 726 30.536 15.963 25.976 1.00 34.40ATOM 417 NE ARG 726 31.176 15.731 27.271 1.00 35.49ATOM 418 CZ ARG 726 32.382 15.196 27.428 1.00 36.20ATOM 419 NH1 ARG 726 32.878 15.024 28.649 1.00 36.46ATOM 420 NH2 ARG 726 33.098 14.846 26.365 1.00 36.56ATOM 421 C ARG 726 27.855 14.480 28.879 1.00 29.93ATOM 422 O ARG 726 28.825 14.378 29.636 1.00 29.51ATOM 423 N ASN 727 26.613 14.212 29.274 1.00 29.89ATOM 424 CA ASN 727 26.374 13.717 30.616 1.00 30.24ATOM 425 CB ASN 727 24.891 13.782 30.968 1.00 30.69ATOM 426 CG ASN 727 24.511 15.087 31.645 1.00 31.99ATOM 427 OD1 ASN 727 23.357 15.539 31.562 1.00 32.19ATOM 428 ND2 ASN 727 25.479 15.699 32.339 1.00 32.26ATOM 429 C ASN 727 26.856 12.279 30.644 1.00 30.26ATOM 430 O ASN 727 27.412 11.835 31.632 1.00 30.96ATOM 431 N LEU 728 26.659 11.562 29.541 1.00 30.22ATOM 432 CA LEU 728 27.080 10.167 29.444 1.00 30.16ATOM 433 CB LEU 728 26.884 9.629 28.020 1.00 29.53ATOM 434 CG LEU 728 25.469 9.476 27.448 1.00 29.44ATOM 435 CD1 LEU 728 25.558 9.204 25.960 1.00 29.24ATOM 436 CD2 LEU 728 24.738 8.351 28.144 1.00 29.16ATOM 437 C LEU 728 28.545 10.049 29.800 1.00 30.48ATOM 438 O LEU 728 29.315 10.995 29.624 1.00 30.21ATOM 439 N HIS 729 28.925 8.884 30.302 1.00 30.85ATOM 440 CA HIS 729 30.310 8.638 30.643 1.00 31.47ATOM 441 CB HIS 729 30.453 7.268 31.327 1.00 31.98ATOM 442 CG HIS 729 31.872 6.884 31.611 1.00 32.66ATOM 443 CD2 HIS 729 32.844 6.406 30.796 1.00 32.89ATOM 444 ND1 HIS 729 32.461 7.060 32.845 1.00 33.17ATOM 445 CE1 HIS 729 33.735 6.713 32.777 1.00 33.16ATOM 446 NE2 HIS 729 33.994 6.314 31.545 1.00 33.32ATOM 447 C HIS 729 31.105 8.650 29.326 1.00 31.63ATOM 448 O HIS 729 30.583 8.279 28.273 1.00 31.40ATOM 449 N VAL 730 32.359 9.078 29.400 1.00 31.76ATOM 450 CA VAL 730 33.250 9.133 28.250 1.00 32.24ATOM 451 CB VAL 730 34.731 9.282 28.713 1.00 32.50ATOM 452 CG1 VAL 730 35.658 9.405 27.508 1.00 32.05ATOM 453 CG2 VAL 730 34.872 10.489 29.632 1.00 32.57ATOM 454 C VAL 730 33.161 7.860 27.408 1.00 33.08ATOM 455 O VAL 730 33.019 7.919 26.181 1.00 33.09ATOM 456 N ASP 731 33.268 6.715 28.085 1.00 33.39ATOM 457 CA ASP 731 33.246 5.400 27.449 1.00 33.76ATOM 458 CB ASP 731 33.558 4.322 28.491 1.00 34.69ATOM 459 CG ASP 731 34.969 4.433 29.033 1.00 36.10ATOM 460 OD1 ASP 731 35.190 4.055 30.214 1.00 36.28ATOM 461 OD2 ASP 731 35.856 4.892 28.270 1.00 36.30ATOM 462 C ASP 731 31.946 5.054 26.738 1.00 33.23ATOM 463 O ASP 731 31.971 4.444 25.674 1.00 33.20ATOM 464 N ASP 732 30.822 5.428 27.344 1.00 32.63ATOM 465 CA ASP 732 29.502 5.172 26.784 1.00 31.98ATOM 466 CB ASP 732 28.418 5.345 27.861 1.00 32.27ATOM 467 CG ASP 732 28.566 4.358 29.018 1.00 32.72ATOM 468 OD1 ASP 732 29.043 3.223 28.783 1.00 33.04ATOM 469 OD2 ASP 732 28.185 4.711 30.159 1.00 32.04ATOM 470 C ASP 732 29.203 6.107 25.606 1.00 31.68ATOM 471 O ASP 732 28.410 5.768 24.722 1.00 31.75ATOM 472 N GLN 733 29.826 7.285 25.604 1.00 30.91ATOM 473 CA GLN 733 29.631 8.249 24.526 1.00 30.18ATOM 474 CB GLN 733 30.481 9.514 24.740 1.00 30.21ATOM 475 CG GLN 733 30.198 10.316 25.996 1.00 31.08ATOM 476 CD GLN 733 31.070 11.577 26.086 1.00 32.11ATOM 477 OE1 GLN 733 32.282 11.528 25.855 1.00 33.33ATOM 478 NE2 GLN 733 30.458 12.699 26.429 1.00 31.97ATOM 479 C GLN 733 30.049 7.610 23.202 1.00 29.54ATOM 480 O GLN 733 29.263 7.553 22.258 1.00 28.86ATOM 481 N MET 734 31.287 7.124 23.146 1.00 29.26ATOM 482 CA MET 734 31.818 6.505 21.929 1.00 29.62ATOM 483 CB MET 734 33.347 6.432 21.993 1.00 31.24ATOM 484 CG MET 734 34.044 7.704 21.512 1.00 34.06ATOM 485 SD MET 734 33.906 8.000 19.707 1.00 37.92ATOM 486 CE MET 734 35.327 7.026 19.055 1.00 36.58ATOM 487 C MET 734 31.253 5.124 21.588 1.00 28.35ATOM 488 O MET 734 31.280 4.722 20.428 1.00 28.45ATOM 489 N ALA 735 30.765 4.398 22.589 1.00 26.73ATOM 490 CA ALA 735 30.181 3.081 22.347 1.00 26.10ATOM 491 CB ALA 735 30.003 2.310 23.669 1.00 26.35ATOM 492 C ALA 735 28.825 3.298 21.676 1.00 24.76ATOM 493 O ALA 735 28.531 2.705 20.653 1.00 24.32ATOM 494 N VAL 736 28.012 4.160 22.272 1.00 24.18ATOM 495 CA VAL 736 26.704 4.487 21.734 1.00 23.42ATOM 496 CB VAL 736 26.022 5.579 22.592 1.00 23.57ATOM 497 CG1 VAL 736 25.268 6.570 21.713 1.00 23.51ATOM 498 CG2 VAL 736 25.071 4.932 23.573 1.00 23.24ATOM 499 C VAL 736 26.895 4.985 20.301 1.00 23.21ATOM 500 O VAL 736 26.228 4.516 19.375 1.00 23.40ATOM 501 N ILE 737 27.827 5.917 20.129 1.00 22.03ATOM 502 CA ILE 737 28.117 6.479 18.816 1.00 21.62ATOM 503 CB ILE 737 29.228 7.550 18.883 1.00 20.18ATOM 504 CG2 ILE 737 29.787 7.795 17.510 1.00 20.01ATOM 505 CG1 ILE 737 28.685 8.855 19.468 1.00 19.45ATOM 506 CD1 ILE 737 29.770 9.894 19.681 1.00 18.31ATOM 507 C ILE 737 28.550 5.428 17.795 1.00 22.21ATOM 508 O ILE 737 28.040 5.403 16.678 1.00 22.12ATOM 509 N GLN 738 29.502 4.576 18.161 1.00 22.07ATOM 510 CA GLN 738 29.949 3.572 17.225 1.00 22.29ATOM 511 CB GLN 738 31.255 2.943 17.701 1.00 23.58ATOM 512 CG GLN 738 32.411 3.940 17.806 1.00 23.70ATOM 513 CD GLN 738 33.698 3.287 18.280 1.00 23.85ATOM 514 OE1 GLN 738 33.682 2.436 19.165 1.00 24.48ATOM 515 NE2 GLN 738 34.819 3.695 17.702 1.00 23.64ATOM 516 C GLN 738 28.891 2.499 16.970 1.00 21.96ATOM 517 O GLN 738 28.771 2.037 15.838 1.00 22.01ATOM 518 N TYR 739 28.112 2.125 17.990 1.00 20.77ATOM 519 CA TYR 739 27.073 1.115 17.800 1.00 19.98ATOM 520 CB TYR 739 26.468 0.627 19.120 1.00 20.07ATOM 521 CG TYR 739 27.407 0.014 20.133 1.00 20.08ATOM 522 CD1 TYR 739 28.400 -0.886 19.754 1.00 20.37ATOM 523 CE1 TYR 739 29.221 -1.484 20.703 1.00 21.09ATOM 524 CD2 TYR 739 27.254 0.295 21.485 1.00 19.66ATOM 525 CE2 TYR 739 28.065 -0.301 22.444 1.00 20.66ATOM 526 CZ TYR 739 29.050 -1.182 22.049 1.00 20.98ATOM 527 OH TYR 739 29.902 -1.706 22.998 1.00 22.42ATOM 528 C TYR 739 25.897 1.621 16.964 1.00 19.75ATOM 529 O TYR 739 25.249 0.845 16.250 1.00 19.75ATOM 530 N SER 740 25.592 2.910 17.063 1.00 18.92ATOM 531 CA SER 740 24.450 3.432 16.316 1.00 18.02ATOM 532 CB SER 740 23.648 4.420 17.181 1.00 18.07ATOM 533 OG SER 740 24.292 5.666 17.302 1.00 18.74ATOM 534 C SER 740 24.831 4.069 14.984 1.00 16.97ATOM 535 O SER 740 23.969 4.442 14.198 1.00 16.64ATOM 536 N TRP 741 26.129 4.150 14.741 1.00 16.05ATOM 537 CA TRP 741 26.689 4.725 13.529 1.00 16.05ATOM 538 CB TRP 741 28.189 4.350 13.492 1.00 17.09ATOM 539 CG TRP 741 29.006 4.764 12.306 1.00 19.02ATOM 540 CD2 TRP 741 30.294 4.238 11.932 1.00 20.22ATOM 541 CE2 TRP 741 30.662 4.848 10.713 1.00 20.50ATOM 542 CE3 TRP 741 31.170 3.302 12.512 1.00 20.91ATOM 543 CD1 TRP 741 28.667 5.657 11.335 1.00 19.78ATOM 544 NE1 TRP 741 29.657 5.711 10.368 1.00 20.54ATOM 545 CZ2 TRP 741 31.864 4.554 10.057 1.00 22.12ATOM 546 CZ3 TRP 741 32.363 3.006 11.865 1.00 21.59ATOM 547 CH2 TRP 741 32.702 3.632 10.643 1.00 22.46ATOM 548 C TRP 741 25.911 4.300 12.257 1.00 15.45ATOM 549 O TRP 741 25.401 5.150 11.526 1.00 14.12ATOM 550 N MET 742 25.791 2.998 12.020 1.00 15.44ATOM 551 CA MET 742 25.090 2.466 10.845 1.00 15.95ATOM 552 CB MET 742 25.100 0.932 10.863 1.00 16.16ATOM 553 CG MET 742 24.447 0.326 9.646 1.00 16.45ATOM 554 SD MET 742 25.477 0.591 8.187 1.00 17.11ATOM 555 CE MET 742 26.513 -0.885 8.352 1.00 16.44ATOM 556 C MET 742 23.635 2.924 10.665 1.00 16.26ATOM 557 O MET 742 23.259 3.451 9.597 1.00 16.31ATOM 558 N GLY 743 22.826 2.683 11.698 1.00 16.23ATOM 559 CA GLY 743 21.422 3.049 11.682 1.00 15.96ATOM 560 C GLY 743 21.210 4.531 11.437 1.00 16.26ATOM 561 O GLY 743 20.346 4.935 10.645 1.00 16.71ATOM 562 N LEU 744 21.990 5.351 12.123 1.00 15.86ATOM 563 CA LEU 744 21.888 6.791 11.952 1.00 15.37ATOM 564 CB LEU 744 22.935 7.512 12.805 1.00 14.98ATOM 565 CG LEU 744 22.689 7.629 14.308 1.00 15.65ATOM 566 CD1 LEU 744 23.916 8.274 14.960 1.00 16.45ATOM 567 CD2 LEU 744 21.447 8.482 14.581 1.00 14.77ATOM 568 C LEU 744 22.100 7.146 10.483 1.00 15.33ATOM 569 O LEU 744 21.350 7.939 9.918 1.00 14.53ATOM 570 N MET 745 23.121 6.551 9.874 1.00 15.35ATOM 571 CA MET 745 23.420 6.819 8.474 1.00 16.27ATOM 572 CB MET 745 24.723 6.138 8.046 1.00 17.35ATOM 573 CG MET 745 25.987 6.659 8.711 1.00 19.23ATOM 574 SD MET 745 27.427 6.326 7.658 1.00 22.31ATOM 575 CE MET 745 27.320 4.566 7.432 1.00 20.16ATOM 576 C MET 745 22.297 6.350 7.540 1.00 16.24ATOM 577 O MET 745 21.939 7.060 6.596 1.00 16.31ATOM 578 N VAL 746 21.755 5.156 7.804 1.00 15.42ATOM 579 CA VAL 746 20.685 4.615 6.981 1.00 14.36ATOM 580 CB VAL 746 20.250 3.215 7.462 1.00 13.88ATOM 581 CG1 VAL 746 18.936 2.830 6.808 1.00 13.61ATOM 582 CG2 VAL 746 21.310 2.198 7.121 1.00 13.23ATOM 583 C VAL 746 19.474 5.532 7.025 1.00 14.30ATOM 584 O VAL 746 18.894 5.835 5.998 1.00 14.06ATOM 585 N PHE 747 19.102 5.959 8.229 1.00 14.31ATOM 586 CA PHE 747 17.953 6.831 8.433 1.00 14.49ATOM 587 CB PHE 747 17.748 7.074 9.923 1.00 13.20ATOM 588 CG PHE 747 16.425 7.677 10.263 1.00 12.24ATOM 589 CD1 PHE 747 15.247 6.951 10.089 1.00 11.83ATOM 590 CD2 PHE 747 16.348 8.954 10.802 1.00 12.05ATOM 591 CE1 PHE 747 14.017 7.491 10.450 1.00 11.38ATOM 592 CE2 PHE 747 15.120 9.498 11.168 1.00 11.97ATOM 593 CZ PHE 747 13.951 8.765 10.991 1.00 10.82ATOM 594 C PHE 747 18.094 8.180 7.715 1.00 15.24ATOM 595 O PHE 747 17.192 8.590 6.994 1.00 15.13ATOM 596 N ALA 748 19.211 8.870 7.930 1.00 15.97ATOM 597 CA ALA 748 19.445 10.154 7.274 1.00 17.37ATOM 598 CB ALA 748 20.765 10.746 7.728 1.00 15.48ATOM 599 C ALA 748 19.460 9.940 5.758 1.00 18.41ATOM 600 O ALA 748 18.875 10.702 4.998 1.00 19.17ATOM 601 N MET 749 20.120 8.882 5.323 1.00 19.85ATOM 602 CA MET 749 20.190 8.612 3.909 1.00 21.36ATOM 603 CB MET 749 21.056 7.388 3.661 1.00 20.95ATOM 604 CG MET 749 21.368 7.151 2.206 1.00 23.14ATOM 605 SD MET 749 20.021 6.300 1.350 1.00 24.54ATOM 606 CE MET 749 20.381 4.591 1.837 1.00 23.82ATOM 607 C MET 749 18.762 8.415 3.395 1.00 22.45ATOM 608 O MET 749 18.405 8.880 2.305 1.00 21.89ATOM 609 N GLY 750 17.938 7.740 4.193 1.00 23.36ATOM 610 CA GLY 750 16.562 7.522 3.787 1.00 23.69ATOM 611 C GLY 750 15.934 8.874 3.507 1.00 24.41ATOM 612 O GLY 750 15.329 9.091 2.451 1.00 23.64ATOM 613 N TRP 751 16.097 9.793 4.461 1.00 25.13ATOM 614 CA TRP 751 15.559 11.144 4.342 1.00 25.53ATOM 615 CB TRP 751 15.937 11.957 5.570 1.00 25.52ATOM 616 CG TRP 751 15.490 13.393 5.533 1.00 24.81ATOM 617 CD2 TRP 751 14.156 13.886 5.715 1.00 24.48ATOM 618 CE2 TRP 751 14.223 15.295 5.669 1.00 24.36ATOM 619 CE3 TRP 751 12.911 13.273 5.913 1.00 24.15ATOM 620 CD1 TRP 751 16.283 14.488 5.380 1.00 24.77ATOM 621 NE1 TRP 751 15.532 15.635 5.464 1.00 24.45ATOM 622 CZ2 TRP 751 13.096 16.104 5.816 1.00 24.20ATOM 623 CZ3 TRP 751 11.794 14.072 6.058 1.00 24.68ATOM 624 CH2 TRP 751 11.893 15.481 6.009 1.00 24.71ATOM 625 C TRP 751 16.068 11.846 3.085 1.00 26.37ATOM 626 O TRP 751 15.279 12.381 2.308 1.00 26.71ATOM 627 N ARG 752 17.384 11.850 2.890 1.00 27.04ATOM 628 CA ARG 752 17.963 12.478 1.713 1.00 27.72ATOM 629 CB ARG 752 19.476 12.286 1.672 1.00 26.90ATOM 630 CG ARG 752 20.229 13.200 2.598 1.00 25.98ATOM 631 CD ARG 752 21.661 13.368 2.123 1.00 25.78ATOM 632 NE ARG 752 22.336 12.086 1.971 1.00 24.53ATOM 633 CZ ARG 752 22.620 11.278 2.986 1.00 24.29ATOM 634 NH1 ARG 752 22.286 11.628 4.222 1.00 23.93ATOM 635 NH2 ARG 752 23.237 10.127 2.764 1.00 23.51ATOM 636 C ARG 752 17.373 11.933 0.427 1.00 28.66ATOM 637 O ARG 752 17.107 12.694 -0.508 1.00 29.23ATOM 638 N SER 753 17.169 10.620 0.367 1.00 29.64ATOM 639 CA SER 753 16.612 10.015 -0.836 1.00 30.86ATOM 640 CB SER 753 16.626 8.485 -0.739 1.00 30.75ATOM 641 OG SER 753 17.950 7.982 -0.831 1.00 30.65ATOM 642 C SER 753 15.196 10.508 -1.049 1.00 31.73ATOM 643 O SER 753 14.681 10.498 -2.162 1.00 31.89ATOM 644 N PHE 754 14.578 10.951 0.034 1.00 33.09ATOM 645 CA PHE 754 13.220 11.457 -0.006 1.00 34.65ATOM 646 CB PHE 754 12.604 11.394 1.391 1.00 34.66ATOM 647 CG PHE 754 11.246 12.019 1.478 1.00 35.49ATOM 648 CD1 PHE 754 10.165 11.463 0.799 1.00 35.64ATOM 649 CD2 PHE 754 11.051 13.185 2.209 1.00 35.56ATOM 650 CE1 PHE 754 8.913 12.061 0.845 1.00 35.75ATOM 651 CE2 PHE 754 9.802 13.792 2.264 1.00 35.98ATOM 652 CZ PHE 754 8.732 13.232 1.581 1.00 36.01ATOM 653 C PHE 754 13.154 12.899 -0.519 1.00 35.79ATOM 654 O PHE 754 12.448 13.193 -1.481 1.00 35.70ATOM 655 N THR 755 13.896 13.789 0.133 1.00 37.07ATOM 656 CA THR 755 13.904 15.204 -0.219 1.00 38.07ATOM 657 CB THR 755 14.561 16.051 0.890 1.00 37.76ATOM 658 OG1 THR 755 15.981 15.846 0.877 1.00 38.00ATOM 659 CG2 THR 755 14.019 15.656 2.243 1.00 37.83ATOM 660 C THR 755 14.626 15.516 -1.521 1.00 38.94ATOM 661 O THR 755 14.855 16.684 -1.834 1.00 39.37ATOM 662 N ASN 756 14.995 14.487 -2.275 1.00 39.70ATOM 663 CA ASN 756 15.693 14.712 -3.533 1.00 40.27ATOM 664 CB ASN 756 17.194 14.427 -3.369 1.00 40.38ATOM 665 CG ASN 756 17.888 15.424 -2.434 1.00 40.95ATOM 666 OD1 ASN 756 17.610 15.469 -1.237 1.00 41.37ATOM 667 ND2 ASN 756 18.792 16.229 -2.986 1.00 41.31ATOM 668 C ASN 756 15.128 13.904 -4.702 1.00 40.62ATOM 669 O ASN 756 14.494 14.460 -5.599 1.00 40.90ATOM 670 N VAL 757 15.337 12.594 -4.687 1.00 41.04ATOM 671 CA VAL 757 14.869 11.743 -5.776 1.00 41.30ATOM 672 CB VAL 757 15.939 10.680 -6.104 1.00 41.48ATOM 673 CG1 VAL 757 17.218 11.363 -6.562 1.00 41.53ATOM 674 CG2 VAL 757 16.226 9.835 -4.878 1.00 41.39ATOM 675 C VAL 757 13.529 11.051 -5.518 1.00 41.34ATOM 676 O VAL 757 13.206 10.046 -6.154 1.00 41.09ATOM 677 N ASN 758 12.747 11.597 -4.593 1.00 41.49ATOM 678 CA ASN 758 11.455 11.012 -4.246 1.00 41.40ATOM 679 CB ASN 758 10.433 11.290 -5.346 1.00 41.86ATOM 680 CG ASN 758 9.848 12.682 -5.251 1.00 42.34ATOM 681 OD1 ASN 758 9.032 12.968 -4.370 1.00 42.45ATOM 682 ND2 ASN 758 10.269 13.561 -6.153 1.00 42.55ATOM 683 C ASN 758 11.548 9.511 -3.993 1.00 41.14ATOM 684 O ASN 758 10.546 8.794 -4.062 1.00 41.19ATOM 685 N SER 759 12.760 9.043 -3.716 1.00 40.61ATOM 686 CA SER 759 13.003 7.639 -3.418 1.00 40.58ATOM 687 CB SER 759 11.925 7.113 -2.462 1.00 40.93ATOM 688 OG SER 759 11.878 7.895 -1.277 1.00 41.37ATOM 689 C SER 759 13.114 6.704 -4.616 1.00 40.19ATOM 690 O SER 759 13.004 5.490 -4.459 1.00 40.32ATOM 691 N ARG 760 13.320 7.255 -5.809 1.00 39.83ATOM 692 CA ARG 760 13.482 6.412 -6.996 1.00 39.13ATOM 693 CB ARG 760 13.278 7.220 -8.289 1.00 40.09ATOM 694 CG ARG 760 13.929 6.590 -9.533 1.00 41.59ATOM 695 CD ARG 760 13.150 6.877 -10.827 1.00 42.76ATOM 696 NE ARG 760 13.856 6.452 -12.047 1.00 44.10ATOM 697 CZ ARG 760 14.317 5.221 -12.290 1.00 44.02ATOM 698 NH1 ARG 760 14.169 4.244 -11.402 1.00 44.29ATOM 699 NH2 ARG 760 14.926 4.966 -13.437 1.00 44.11ATOM 700 C ARG 760 14.897 5.843 -6.951 1.00 37.86ATOM 701 O ARG 760 15.200 4.841 -7.603 1.00 37.94ATOM 702 N MET 761 15.760 6.489 -6.169 1.00 36.18ATOM 703 CA MET 761 17.144 6.040 -6.030 1.00 34.54ATOM 704 CB MET 761 18.026 6.693 -7.095 1.00 34.81ATOM 705 CG MET 761 17.649 6.378 -8.531 1.00 35.67ATOM 706 SD MET 761 18.836 7.089 -9.710 1.00 35.66ATOM 707 CE MET 761 18.291 8.796 -9.734 1.00 35.50ATOM 708 C MET 761 17.727 6.352 -4.652 1.00 32.75ATOM 709 O MET 761 17.347 7.329 -4.009 1.00 32.64ATOM 710 N LEU 762 18.661 5.521 -4.211 1.00 30.58ATOM 711 CA LEU 762 19.309 5.728 -2.924 1.00 28.84ATOM 712 CB LEU 762 19.967 4.435 -2.457 1.00 28.33ATOM 713 CG LEU 762 19.019 3.248 -2.303 1.00 28.15ATOM 714 CD1 LEU 762 19.810 2.045 -1.847 1.00 28.12ATOM 715 CD2 LEU 762 17.924 3.575 -1.308 1.00 27.94ATOM 716 C LEU 762 20.356 6.838 -3.040 1.00 27.76ATOM 717 O LEU 762 21.341 6.713 -3.779 1.00 27.12ATOM 718 N TYR 763 20.135 7.921 -2.302 1.00 26.72ATOM 719 CA TYR 763 21.041 9.071 -2.318 1.00 26.03ATOM 720 CB TYR 763 20.224 10.355 -2.181 1.00 26.73ATOM 721 CG TYR 763 20.832 11.570 -2.836 1.00 28.00ATOM 722 CD1 TYR 763 20.532 11.894 -4.159 1.00 28.78ATOM 723 CE1 TYR 763 21.064 13.037 -4.764 1.00 29.17ATOM 724 CD2 TYR 763 21.686 12.414 -2.131 1.00 28.81ATOM 725 CE2 TYR 763 22.226 13.561 -2.729 1.00 29.70ATOM 726 CZ TYR 763 21.907 13.865 -4.045 1.00 29.56ATOM 727 OH TYR 763 22.410 15.005 -4.629 1.00 30.24ATOM 728 C TYR 763 22.074 9.000 -1.180 1.00 25.05ATOM 729 O TYR 763 21.886 9.607 -0.130 1.00 24.70ATOM 730 N PHE 764 23.154 8.253 -1.386 1.00 23.85ATOM 731 CA PHE 764 24.176 8.138 -0.363 1.00 23.36ATOM 732 CB PHE 764 25.167 7.026 -0.687 1.00 22.20ATOM 733 CG PHE 764 24.592 5.665 -0.577 1.00 20.93ATOM 734 CD1 PHE 764 24.141 4.997 -1.703 1.00 21.03ATOM 735 CD2 PHE 764 24.484 5.049 0.654 1.00 20.64ATOM 736 CE1 PHE 764 23.590 3.728 -1.600 1.00 21.11ATOM 737 CE2 PHE 764 23.936 3.785 0.765 1.00 20.71ATOM 738 CZ PHE 764 23.489 3.123 -0.360 1.00 20.65ATOM 739 C PHE 764 24.921 9.442 -0.246 1.00 23.54ATOM 740 O PHE 764 25.270 9.866 0.848 1.00 23.77ATOM 741 N ALA 765 25.154 10.067 -1.394 1.00 23.97ATOM 742 CA ALA 765 25.854 11.346 -1.488 1.00 24.26ATOM 743 CB ALA 765 27.346 11.142 -1.219 1.00 24.01ATOM 744 C ALA 765 25.627 11.880 -2.909 1.00 24.66ATOM 745 O ALA 765 25.211 11.130 -3.789 1.00 24.88ATOM 746 N PRO 766 25.888 13.178 -3.153 1.00 25.03ATOM 747 CD PRO 766 26.345 14.222 -2.220 1.00 25.22ATOM 748 CA PRO 766 25.687 13.740 -4.496 1.00 25.14ATOM 749 CB PRO 766 26.159 15.190 -4.335 1.00 25.71ATOM 750 CG PRO 766 25.841 15.485 -2.888 1.00 25.20ATOM 751 C PRO 766 26.485 12.980 -5.554 1.00 25.17ATOM 752 O PRO 766 25.984 12.693 -6.651 1.00 25.08ATOM 753 N ASP 767 27.721 12.634 -5.208 1.00 25.17ATOM 754 CA ASP 767 28.600 11.898 -6.117 1.00 25.59ATOM 755 CB ASP 767 30.058 12.292 -5.858 1.00 25.95ATOM 756 CG ASP 767 30.531 11.898 -4.470 1.00 27.34ATOM 757 OD1 ASP 767 29.780 12.093 -3.487 1.00 26.89ATOM 758 OD2 ASP 767 31.668 11.400 -4.355 1.00 29.03ATOM 759 C ASP 767 28.457 10.374 -6.012 1.00 25.16ATOM 760 O ASP 767 29.215 9.644 -6.636 1.00 25.56ATOM 761 N LEU 768 27.507 9.891 -5.214 1.00 24.75ATOM 762 CA LEU 768 27.298 8.453 -5.076 1.00 24.23ATOM 763 CB LEU 768 28.070 7.909 -3.870 1.00 23.92ATOM 764 CG LEU 768 28.183 6.378 -3.771 1.00 23.88ATOM 765 CD1 LEU 768 28.910 5.819 -4.974 1.00 23.45ATOM 766 CD2 LEU 768 28.943 6.011 -2.523 1.00 24.21ATOM 767 C LEU 768 25.808 8.129 -4.944 1.00 24.57ATOM 768 O LEU 768 25.285 7.931 -3.846 1.00 24.30ATOM 769 N VAL 769 25.133 8.081 -6.088 1.00 24.78ATOM 770 CA VAL 769 23.702 7.802 -6.149 1.00 24.65ATOM 771 CB VAL 769 22.998 8.807 -7.089 1.00 24.73ATOM 772 CG1 VAL 769 21.480 8.621 -7.031 1.00 24.37ATOM 773 CG2 VAL 769 23.398 10.245 -6.700 1.00 24.01ATOM 774 C VAL 769 23.560 6.391 -6.698 1.00 24.90ATOM 775 O VAL 769 24.156 6.061 -7.717 1.00 25.44ATOM 776 N PHE 770 22.794 5.554 -6.007 1.00 24.72ATOM 777 CA PHE 770 22.615 4.180 -6.434 1.00 24.40ATOM 778 CB PHE 770 22.631 3.224 -5.243 1.00 24.46ATOM 779 CG PHE 770 23.994 2.714 -4.867 1.00 23.68ATOM 780 CD1 PHE 770 25.125 3.522 -4.993 1.00 22.58ATOM 781 CD2 PHE 770 24.128 1.452 -4.294 1.00 23.29ATOM 782 CE1 PHE 770 26.363 3.087 -4.552 1.00 22.46ATOM 783 CE2 PHE 770 25.370 1.003 -3.841 1.00 23.62ATOM 784 CZ PHE 770 26.497 1.833 -3.974 1.00 23.15ATOM 785 C PHE 770 21.323 3.959 -7.167 1.00 24.70ATOM 786 O PHE 770 20.237 4.104 -6.593 1.00 24.80ATOM 787 N ASN 771 21.449 3.604 -8.438 1.00 24.57ATOM 788 CA ASN 771 20.298 3.288 -9.259 1.00 24.55ATOM 789 CB ASN 771 20.531 3.729 -10.699 1.00 24.45ATOM 790 CG ASN 771 21.892 3.329 -11.216 1.00 24.66ATOM 791 OD1 ASN 771 22.551 2.424 -10.678 1.00 24.49ATOM 792 ND2 ASN 771 22.321 3.991 -12.277 1.00 24.40ATOM 793 C ASN 771 20.195 1.770 -9.175 1.00 24.68ATOM 794 O ASN 771 21.009 1.131 -8.510 1.00 24.39ATOM 795 N GLU 772 19.211 1.185 -9.842 1.00 25.37ATOM 796 CA GLU 772 19.052 -0.263 -9.790 1.00 25.97ATOM 797 CB GLU 772 17.885 -0.698 -10.673 1.00 26.94ATOM 798 CG GLU 772 16.519 -0.461 -10.013 1.00 28.24ATOM 799 CD GLU 772 15.988 -1.704 -9.306 1.00 29.05ATOM 800 OE1 GLU 772 15.347 -1.562 -8.235 1.00 29.60ATOM 801 OE2 GLU 772 16.203 -2.819 -9.835 1.00 29.05ATOM 802 C GLU 772 20.318 -0.987 -10.190 1.00 26.14ATOM 803 O GLU 772 20.737 -1.934 -9.518 1.00 26.09ATOM 804 N TYR 773 20.948 -0.530 -11.270 1.00 25.97ATOM 805 CA TYR 773 22.166 -1.170 -11.734 1.00 25.56ATOM 806 CB TYR 773 22.734 -0.445 -12.944 1.00 26.25ATOM 807 CG TYR 773 24.033 -1.034 -13.428 1.00 25.78ATOM 808 CD1 TYR 773 24.073 -2.281 -14.040 1.00 25.69ATOM 809 CE1 TYR 773 25.282 -2.830 -14.469 1.00 26.68ATOM 810 CD2 TYR 773 25.228 -0.344 -13.256 1.00 26.64ATOM 811 CE2 TYR 773 26.448 -0.876 -13.683 1.00 26.53ATOM 812 CZ TYR 773 26.469 -2.113 -14.286 1.00 26.86ATOM 813 OH TYR 773 27.676 -2.624 -14.705 1.00 26.83ATOM 814 C TYR 773 23.222 -1.234 -10.648 1.00 25.39ATOM 815 O TYR 773 23.823 -2.286 -10.420 1.00 25.85ATOM 816 N ARG 774 23.468 -0.117 -9.975 1.00 24.83ATOM 817 CA ARG 774 24.467 -0.129 -8.913 1.00 24.13ATOM 818 CB ARG 774 24.806 1.293 -8.493 1.00 23.53ATOM 819 CG ARG 774 25.745 1.963 -9.465 1.00 23.97ATOM 820 CD ARG 774 25.760 3.472 -9.277 1.00 24.07ATOM 821 NE ARG 774 26.915 4.069 -9.934 1.00 24.01ATOM 822 CZ ARG 774 27.280 5.332 -9.778 1.00 23.94ATOM 823 NH1 ARG 774 26.576 6.124 -8.989 1.00 24.20ATOM 824 NH2 ARG 774 28.350 5.797 -10.405 1.00 24.95ATOM 825 C ARG 774 24.016 -0.965 -7.714 1.00 23.78ATOM 826 O ARG 774 24.836 -1.553 -7.027 1.00 23.53ATOM 827 N MET 775 22.714 -1.019 -7.470 1.00 23.55ATOM 828 CA MET 775 22.189 -1.818 -6.375 1.00 24.24ATOM 829 CB MET 775 20.680 -1.654 -6.298 1.00 23.35ATOM 830 CG MET 775 20.279 -0.409 -5.602 1.00 22.56ATOM 831 SD MET 775 18.562 -0.102 -5.803 1.00 23.81ATOM 832 CE MET 775 18.596 1.595 -6.444 1.00 23.32ATOM 833 C MET 775 22.544 -3.302 -6.556 1.00 25.19ATOM 834 O MET 775 22.837 -4.011 -5.589 1.00 24.45ATOM 835 N HIS 776 22.530 -3.757 -7.806 1.00 26.18ATOM 836 CA HIS 776 22.845 -5.141 -8.119 1.00 26.92ATOM 837 CB HIS 776 22.313 -5.505 -9.510 1.00 27.27ATOM 838 CG HIS 776 22.615 -6.914 -9.913 1.00 28.49ATOM 839 CD2 HIS 776 21.882 -8.049 -9.798 1.00 28.49ATOM 840 ND1 HIS 776 23.841 -7.299 -10.415 1.00 28.47ATOM 841 CE1 HIS 776 23.851 -8.611 -10.586 1.00 28.94ATOM 842 NE2 HIS 776 22.675 -9.089 -10.219 1.00 29.04ATOM 843 C HIS 776 24.344 -5.376 -8.070 1.00 27.70ATOM 844 O HIS 776 24.818 -6.350 -7.481 1.00 28.14ATOM 845 N LYS 777 25.086 -4.474 -8.699 1.00 28.16ATOM 846 CA LYS 777 26.536 -4.555 -8.760 1.00 28.25ATOM 847 CB LYS 777 27.050 -3.468 -9.702 1.00 28.87ATOM 848 CG LYS 777 26.568 -3.632 -11.138 1.00 29.22ATOM 849 CD LYS 777 27.637 -4.263 -12.030 1.00 29.26ATOM 850 CE LYS 777 28.063 -5.643 -11.572 1.00 29.02ATOM 851 NZ LYS 777 29.216 -6.132 -12.387 1.00 29.65ATOM 852 C LYS 777 27.234 -4.440 -7.398 1.00 28.38ATOM 853 O LYS 777 28.306 -5.006 -7.196 1.00 28.33ATOM 854 N SER 778 26.638 -3.701 -6.468 1.00 28.47ATOM 855 CA SER 778 27.227 -3.542 -5.143 1.00 28.59ATOM 856 CB SER 778 26.574 -2.369 -4.408 1.00 28.41ATOM 857 OG SER 778 25.199 -2.621 -4.172 1.00 27.42ATOM 858 C SER 778 27.043 -4.820 -4.323 1.00 29.24ATOM 859 O SER 778 27.756 -5.039 -3.352 1.00 29.39ATOM 860 N ARG 779 26.078 -5.645 -4.733 1.00 29.69ATOM 861 CA ARG 779 25.739 -6.904 -4.081 1.00 30.16ATOM 862 CB ARG 779 26.998 -7.730 -3.817 1.00 30.77ATOM 863 CG ARG 779 27.686 -8.208 -5.085 1.00 30.83ATOM 864 CD ARG 779 28.959 -8.974 -4.796 1.00 31.77ATOM 865 NE ARG 779 29.699 -9.207 -6.030 1.00 33.22ATOM 866 CZ ARG 779 30.984 -9.547 -6.096 1.00 33.96ATOM 867 NH1 ARG 779 31.700 -9.705 -4.987 1.00 33.90ATOM 868 NH2 ARG 779 31.562 -9.699 -7.283 1.00 34.13ATOM 869 C ARG 779 24.942 -6.698 -2.790 1.00 30.89ATOM 870 O ARG 779 24.962 -7.541 -1.886 1.00 30.62ATOM 871 N MET 780 24.232 -5.570 -2.729 1.00 31.21ATOM 872 CA MET 780 23.384 -5.221 -1.592 1.00 31.28ATOM 873 CB MET 780 23.948 -4.017 -0.832 1.00 32.57ATOM 874 CG MET 780 25.288 -4.215 -0.172 1.00 34.02ATOM 875 SD MET 780 25.814 -2.649 0.565 1.00 37.00ATOM 876 CE MET 780 26.603 -1.893 -0.815 1.00 34.95ATOM 877 C MET 780 22.010 -4.839 -2.137 1.00 30.81ATOM 878 O MET 780 21.414 -3.841 -1.718 1.00 31.05ATOM 879 N TYR 781 21.497 -5.621 -3.074 1.00 29.92ATOM 880 CA TYR 781 20.208 -5.283 -3.651 1.00 29.23ATOM 881 CB TYR 781 19.920 -6.156 -4.882 1.00 28.90ATOM 882 CG TYR 781 18.721 -5.689 -5.670 1.00 28.52ATOM 883 CD1 TYR 781 18.851 -4.762 -6.701 1.00 28.60ATOM 884 CE1 TYR 781 17.726 -4.311 -7.408 1.00 28.68ATOM 885 CD2 TYR 781 17.443 -6.152 -5.359 1.00 28.60ATOM 886 CE2 TYR 781 16.318 -5.706 -6.051 1.00 28.33ATOM 887 CZ TYR 781 16.461 -4.791 -7.071 1.00 28.53ATOM 888 OH TYR 781 15.337 -4.364 -7.748 1.00 28.76ATOM 889 C TYR 781 19.087 -5.407 -2.620 1.00 28.96ATOM 890 O TYR 781 18.246 -4.513 -2.513 1.00 28.45ATOM 891 N SER 782 19.068 -6.504 -1.862 1.00 28.78ATOM 892 CA SER 782 18.030 -6.678 -0.835 1.00 28.74ATOM 893 CB SER 782 18.209 -8.004 -0.100 1.00 29.02ATOM 894 OG SER 782 18.036 -9.090 -0.987 1.00 30.66ATOM 895 C SER 782 18.044 -5.531 0.187 1.00 27.95ATOM 896 O SER 782 17.045 -4.839 0.363 1.00 28.09ATOM 897 N GLN 783 19.170 -5.325 0.855 1.00 27.40ATOM 898 CA GLN 783 19.249 -4.244 1.836 1.00 27.42ATOM 899 CB GLN 783 20.669 -4.113 2.397 1.00 27.83ATOM 900 CG GLN 783 21.268 -5.393 2.978 1.00 28.33ATOM 901 CD GLN 783 21.844 -6.302 1.919 1.00 29.14ATOM 902 OE1 GLN 783 22.658 -7.184 2.215 1.00 29.90ATOM 903 NE2 GLN 783 21.426 -6.099 0.672 1.00 28.96ATOM 904 C GLN 783 18.840 -2.924 1.177 1.00 26.96ATOM 905 O GLN 783 18.124 -2.114 1.781 1.00 26.53ATOM 906 N CYS 784 19.290 -2.719 -0.064 1.00 26.46ATOM 907 CA CYS 784 18.963 -1.506 -0.808 1.00 26.18ATOM 908 CB CYS 784 19.695 -1.488 -2.159 1.00 27.17ATOM 909 SG CYS 784 21.458 -1.025 -2.047 1.00 28.41ATOM 910 C CYS 784 17.452 -1.389 -1.002 1.00 25.21ATOM 911 O CYS 784 16.901 -0.290 -0.952 1.00 24.95ATOM 912 N VAL 785 16.789 -2.524 -1.210 1.00 24.67ATOM 913 CA VAL 785 15.330 -2.554 -1.351 1.00 24.38ATOM 914 CB VAL 785 14.821 -3.960 -1.738 1.00 24.36ATOM 915 CG1 VAL 785 13.455 -4.230 -1.081 1.00 24.20ATOM 916 CG2 VAL 785 14.705 -4.055 -3.247 1.00 23.60ATOM 917 C VAL 785 14.698 -2.157 -0.021 1.00 23.98ATOM 918 O VAL 785 13.705 -1.441 0.020 1.00 23.63ATOM 919 N ARG 786 15.280 -2.646 1.067 1.00 24.16ATOM 920 CA ARG 786 14.808 -2.304 2.411 1.00 24.19ATOM 921 CB ARG 786 15.667 -3.016 3.465 1.00 24.76ATOM 922 CG ARG 786 15.663 -4.537 3.386 1.00 25.63ATOM 923 CD ARG 786 14.617 -5.109 4.314 1.00 26.26ATOM 924 NE ARG 786 15.149 -6.186 5.141 1.00 26.47ATOM 925 CZ ARG 786 14.769 -6.414 6.396 1.00 26.71ATOM 926 NH1 ARG 786 13.861 -5.637 6.970 1.00 26.62ATOM 927 NH2 ARG 786 15.283 -7.426 7.074 1.00 26.60ATOM 928 C ARG 786 14.934 -0.783 2.613 1.00 23.52ATOM 929 O ARG 786 14.015 -0.128 3.087 1.00 23.13ATOM 930 N MET 787 16.079 -0.227 2.236 1.00 23.46ATOM 931 CA MET 787 16.326 1.201 2.404 1.00 24.21ATOM 932 CB MET 787 17.799 1.506 2.153 1.00 24.32ATOM 933 CG MET 787 18.695 0.872 3.191 1.00 25.11ATOM 934 SD MET 787 20.411 1.249 2.977 1.00 26.06ATOM 935 CE MET 787 20.960 -0.200 2.082 1.00 25.69ATOM 936 C MET 787 15.443 2.082 1.535 1.00 24.88ATOM 937 O MET 787 14.947 3.113 1.999 1.00 24.39ATOM 938 N ARG 788 15.260 1.675 0.278 1.00 25.61ATOM 939 CA ARG 788 14.399 2.394 -0.651 1.00 26.64ATOM 940 CB ARG 788 14.361 1.661 -2.003 1.00 27.51ATOM 941 CG ARG 788 13.561 2.371 -3.089 1.00 28.69ATOM 942 CD ARG 788 14.374 2.537 -4.378 1.00 29.41ATOM 943 NE ARG 788 14.059 1.556 -5.419 1.00 29.78ATOM 944 CZ ARG 788 14.634 1.548 -6.626 1.00 31.03ATOM 945 NH1 ARG 788 15.549 2.465 -6.935 1.00 30.51ATOM 946 NH2 ARG 788 14.298 0.631 -7.532 1.00 30.16ATOM 947 C ARG 788 13.016 2.401 0.007 1.00 26.84ATOM 948 O ARG 788 12.328 3.418 0.047 1.00 26.40ATOM 949 N HIS 789 12.632 1.251 0.545 1.00 27.75ATOM 950 CA HIS 789 11.359 1.104 1.233 1.00 29.39ATOM 951 CB HIS 789 11.238 -0.300 1.811 1.00 30.70ATOM 952 CG HIS 789 9.968 -0.996 1.447 1.00 32.08ATOM 953 CD2 HIS 789 8.916 -1.387 2.205 1.00 32.40ATOM 954 ND1 HIS 789 9.685 -1.396 0.157 1.00 32.78ATOM 955 CE1 HIS 789 8.513 -2.009 0.139 1.00 33.40ATOM 956 NE2 HIS 789 8.026 -2.017 1.369 1.00 33.45ATOM 957 C HIS 789 11.275 2.120 2.373 1.00 29.90ATOM 958 O HIS 789 10.274 2.829 2.513 1.00 29.93ATOM 959 N LEU 790 12.328 2.173 3.192 1.00 30.02ATOM 960 CA LEU 790 12.390 3.115 4.307 1.00 30.13ATOM 961 CB LEU 790 13.775 3.071 4.956 1.00 30.30ATOM 962 CG LEU 790 14.142 4.222 5.896 1.00 30.27ATOM 963 CD1 LEU 790 13.147 4.322 7.029 1.00 30.03ATOM 964 CD2 LEU 790 15.536 3.978 6.445 1.00 31.35ATOM 965 C LEU 790 12.107 4.533 3.836 1.00 30.25ATOM 966 O LEU 790 11.194 5.189 4.325 1.00 30.14ATOM 967 N SER 791 12.911 5.000 2.890 1.00 30.62ATOM 968 CA SER 791 12.759 6.334 2.338 1.00 31.31ATOM 969 CB SER 791 13.661 6.504 1.123 1.00 31.61ATOM 970 OG SER 791 13.224 5.654 0.082 1.00 32.91ATOM 971 C SER 791 11.318 6.603 1.920 1.00 31.63ATOM 972 O SER 791 10.747 7.626 2.290 1.00 32.03ATOM 973 N GLN 792 10.734 5.696 1.138 1.00 31.71ATOM 974 CA GLN 792 9.354 5.873 0.687 1.00 31.71ATOM 975 CB GLN 792 8.909 4.666 -0.150 1.00 31.94ATOM 976 CG GLN 792 9.637 4.593 -1.492 1.00 32.57ATOM 977 CD GLN 792 9.418 3.282 -2.223 1.00 33.30ATOM 978 OE1 GLN 792 8.385 3.073 -2.860 1.00 33.62ATOM 979 NE2 GLN 792 10.394 2.384 -2.128 1.00 33.08ATOM 980 C GLN 792 8.417 6.107 1.870 1.00 31.60ATOM 981 O GLN 792 7.459 6.881 1.766 1.00 31.38ATOM 982 N GLU 793 8.706 5.455 2.997 1.00 31.29ATOM 983 CA GLU 793 7.913 5.629 4.216 1.00 30.78ATOM 984 CB GLU 793 8.490 4.782 5.353 1.00 31.16ATOM 985 CG GLU 793 8.422 3.301 5.099 1.00 31.63ATOM 986 CD GLU 793 7.024 2.753 5.256 1.00 32.41ATOM 987 OE1 GLU 793 6.056 3.549 5.178 1.00 32.89ATOM 988 OE2 GLU 793 6.892 1.523 5.447 1.00 32.77ATOM 989 C GLU 793 7.927 7.101 4.630 1.00 30.41ATOM 990 O GLU 793 6.959 7.609 5.202 1.00 30.34ATOM 991 N PHE 794 9.032 7.787 4.355 1.00 29.94ATOM 992 CA PHE 794 9.119 9.195 4.703 1.00 29.89ATOM 993 CB PHE 794 10.498 9.762 4.367 1.00 29.61ATOM 994 CG PHE 794 11.586 9.331 5.316 1.00 29.83ATOM 995 CD1 PHE 794 11.472 9.567 6.683 1.00 29.77ATOM 996 CD2 PHE 794 12.722 8.684 4.848 1.00 29.90ATOM 997 CE1 PHE 794 12.466 9.161 7.561 1.00 29.72ATOM 998 CE2 PHE 794 13.722 8.274 5.726 1.00 30.02ATOM 999 CZ PHE 794 13.592 8.513 7.083 1.00 29.58ATOM 1000 C PHE 794 8.057 9.943 3.922 1.00 30.47ATOM 1001 O PHE 794 7.721 11.075 4.248 1.00 30.71ATOM 1002 N GLY 795 7.532 9.296 2.883 1.00 31.23ATOM 1003 CA GLY 795 6.513 9.910 2.053 1.00 31.91ATOM 1004 C GLY 795 5.101 9.482 2.410 1.00 32.71ATOM 1005 O GLY 795 4.219 10.322 2.557 1.00 32.69ATOM 1006 N TRP 796 4.875 8.181 2.557 1.00 33.17ATOM 1007 CA TRP 796 3.539 7.701 2.897 1.00 34.04ATOM 1008 CB TRP 796 3.490 6.176 2.820 1.00 33.54ATOM 1009 CG TRP 796 3.880 5.642 1.484 1.00 33.47ATOM 1010 CD2 TRP 796 4.706 4.499 1.223 1.00 33.26ATOM 1011 CE2 TRP 796 4.779 4.347 -0.183 1.00 32.92ATOM 1012 CE3 TRP 796 5.391 3.587 2.039 1.00 33.53ATOM 1013 CD1 TRP 796 3.497 6.125 0.259 1.00 33.23ATOM 1014 NE1 TRP 796 4.033 5.351 -0.743 1.00 32.89ATOM 1015 CZ2 TRP 796 5.509 3.320 -0.793 1.00 32.88ATOM 1016 CZ3 TRP 796 6.124 2.556 1.426 1.00 33.73ATOM 1017 CH2 TRP 796 6.172 2.438 0.022 1.00 33.34ATOM 1018 C TRP 796 3.079 8.168 4.283 1.00 34.95ATOM 1019 O TRP 796 1.883 8.130 4.596 1.00 35.51ATOM 1020 N LEU 797 4.026 8.620 5.105 1.00 35.59ATOM 1021 CA LEU 797 3.712 9.097 6.451 1.00 35.60ATOM 1022 CB LEU 797 4.672 8.487 7.466 1.00 35.55ATOM 1023 CG LEU 797 4.539 6.978 7.667 1.00 35.46ATOM 1024 CD1 LEU 797 5.745 6.465 8.443 1.00 35.46ATOM 1025 CD2 LEU 797 3.232 6.671 8.390 1.00 35.11ATOM 1026 C LEU 797 3.794 10.610 6.545 1.00 35.92ATOM 1027 O LEU 797 3.574 11.182 7.612 1.00 36.29ATOM 1028 N GLN 798 4.103 11.257 5.427 1.00 36.20ATOM 1029 CA GLN 798 4.224 12.711 5.397 1.00 36.28ATOM 1030 CB GLN 798 2.830 13.377 5.366 1.00 37.02ATOM 1031 CG GLN 798 2.233 13.503 3.939 1.00 38.04ATOM 1032 CD GLN 798 0.757 13.919 3.908 1.00 38.46ATOM 1033 OE1 GLN 798 -0.113 13.231 4.458 1.00 39.04ATOM 1034 NE2 GLN 798 0.472 15.036 3.247 1.00 38.17ATOM 1035 C GLN 798 5.033 13.185 6.598 1.00 35.87ATOM 1036 O GLN 798 4.637 14.099 7.321 1.00 36.50ATOM 1037 N ILE 799 6.179 12.543 6.794 1.00 35.08ATOM 1038 CA ILE 799 7.084 12.869 7.885 1.00 34.09ATOM 1039 CB ILE 799 8.205 11.824 7.982 1.00 33.96ATOM 1040 CG2 ILE 799 9.294 12.288 8.934 1.00 33.52ATOM 1041 CG1 ILE 799 7.598 10.504 8.439 1.00 34.19ATOM 1042 CD1 ILE 799 8.575 9.407 8.549 1.00 35.01ATOM 1043 C ILE 799 7.691 14.247 7.694 1.00 33.51ATOM 1044 O ILE 799 8.244 14.547 6.645 1.00 33.24ATOM 1045 N THR 800 7.587 15.074 8.728 1.00 33.31ATOM 1046 CA THR 800 8.102 16.436 8.700 1.00 33.05ATOM 1047 CB THR 800 7.351 17.341 9.717 1.00 33.44ATOM 1048 OG1 THR 800 7.803 17.043 11.048 1.00 33.14ATOM 1049 CG2 THR 800 5.840 17.113 9.636 1.00 32.47ATOM 1050 C THR 800 9.582 16.515 9.050 1.00 33.21ATOM 1051 O THR 800 10.166 15.577 9.599 1.00 33.40ATOM 1052 N PRO 801 10.214 17.644 8.719 1.00 33.07ATOM 1053 CD PRO 801 9.726 18.642 7.748 1.00 33.01ATOM 1054 CA PRO 801 11.630 17.858 9.007 1.00 32.90ATOM 1055 CB PRO 801 11.891 19.229 8.386 1.00 32.72ATOM 1056 CG PRO 801 11.012 19.196 7.189 1.00 32.68ATOM 1057 C PRO 801 11.886 17.841 10.521 1.00 32.91ATOM 1058 O PRO 801 12.899 17.314 10.995 1.00 33.12ATOM 1059 N GLN 802 10.967 18.426 11.281 1.00 32.37ATOM 1060 CA GLN 802 11.117 18.458 12.729 1.00 31.71ATOM 1061 CB GLN 802 10.090 19.425 13.340 1.00 32.11ATOM 1062 CG GLN 802 10.276 20.925 12.948 1.00 32.69ATOM 1063 CD GLN 802 9.954 21.244 11.464 1.00 33.21ATOM 1064 OE1 GLN 802 8.898 20.871 10.943 1.00 33.11ATOM 1065 NE2 GLN 802 10.865 21.956 10.798 1.00 33.53ATOM 1066 C GLN 802 10.987 17.045 13.338 1.00 31.06ATOM 1067 O GLN 802 11.680 16.711 14.305 1.00 31.17ATOM 1068 N GLU 803 10.109 16.217 12.775 1.00 29.88ATOM 1069 CA GLU 803 9.935 14.849 13.269 1.00 28.79ATOM 1070 CB GLU 803 8.750 14.154 12.587 1.00 29.29ATOM 1071 CG GLU 803 7.378 14.677 12.936 1.00 30.44ATOM 1072 CD GLU 803 6.286 13.977 12.145 1.00 30.78ATOM 1073 OE1 GLU 803 6.277 14.099 10.905 1.00 29.94ATOM 1074 OE2 GLU 803 5.440 13.295 12.766 1.00 32.29ATOM 1075 C GLU 803 11.198 14.058 12.940 1.00 27.63ATOM 1076 O GLU 803 11.743 13.358 13.783 1.00 27.67ATOM 1077 N PHE 804 11.644 14.167 11.694 1.00 25.86ATOM 1078 CA PHE 804 12.835 13.472 11.252 1.00 24.53ATOM 1079 CB PHE 804 13.176 13.850 9.803 1.00 23.88ATOM 1080 CG PHE 804 14.603 13.578 9.439 1.00 23.21ATOM 1081 CD1 PHE 804 15.098 12.280 9.449 1.00 22.70ATOM 1082 CD2 PHE 804 15.475 14.625 9.164 1.00 23.07ATOM 1083 CE1 PHE 804 16.436 12.031 9.199 1.00 22.58ATOM 1084 CE2 PHE 804 16.823 14.384 8.909 1.00 22.21ATOM 1085 CZ PHE 804 17.303 13.091 8.929 1.00 22.63ATOM 1086 C PHE 804 14.044 13.755 12.146 1.00 23.92ATOM 1087 O PHE 804 14.797 12.841 12.480 1.00 23.49ATOM 1088 N LEU 805 14.242 15.013 12.517 1.00 23.43ATOM 1089 CA LEU 805 15.377 15.360 13.362 1.00 23.07ATOM 1090 CB LEU 805 15.572 16.881 13.432 1.00 22.40ATOM 1091 CG LEU 805 15.862 17.582 12.100 1.00 22.11ATOM 1092 CD1 LEU 805 16.020 19.075 12.339 1.00 22.35ATOM 1093 CD2 LEU 805 17.104 17.007 11.441 1.00 21.68ATOM 1094 C LEU 805 15.240 14.791 14.761 1.00 23.01ATOM 1095 O LEU 805 16.231 14.404 15.358 1.00 23.29ATOM 1096 N CYS 806 14.028 14.731 15.301 1.00 23.32ATOM 1097 CA CYS 806 13.872 14.151 16.638 1.00 23.74ATOM 1098 CB CYS 806 12.469 14.379 17.179 1.00 24.34ATOM 1099 SG CYS 806 12.141 16.076 17.527 1.00 30.40ATOM 1100 C CYS 806 14.145 12.649 16.605 1.00 22.67ATOM 1101 O CYS 806 14.877 12.117 17.447 1.00 22.58ATOM 1102 N MET 807 13.543 11.971 15.637 1.00 21.64ATOM 1103 CA MET 807 13.724 10.532 15.503 1.00 21.18ATOM 1104 CB MET 807 12.919 9.991 14.313 1.00 22.00ATOM 1105 CG MET 807 11.403 10.114 14.463 1.00 23.29ATOM 1106 SD MET 807 10.507 9.386 13.019 1.00 25.08ATOM 1107 CE MET 807 10.295 10.783 12.018 1.00 24.91ATOM 1108 C MET 807 15.204 10.193 15.330 1.00 19.80ATOM 1109 O MET 807 15.698 9.267 15.950 1.00 19.29ATOM 1110 N LYS 808 15.900 10.950 14.488 1.00 18.78ATOM 1111 CA LYS 808 17.321 10.730 14.250 1.00 18.18ATOM 1112 CB LYS 808 17.877 11.789 13.284 1.00 17.70ATOM 1113 CG LYS 808 19.376 11.652 13.044 1.00 18.55ATOM 1114 CD LYS 808 19.775 11.948 11.583 1.00 18.83ATOM 1115 CE LYS 808 19.711 13.425 11.271 1.00 17.98ATOM 1116 NZ LYS 808 20.547 14.166 12.258 1.00 18.71ATOM 1117 C LYS 808 18.063 10.786 15.588 1.00 17.76ATOM 1118 O LYS 808 18.823 9.880 15.921 1.00 16.45ATOM 1119 N ALA 809 17.829 11.853 16.347 1.00 17.98ATOM 1120 CA ALA 809 18.443 12.011 17.661 1.00 18.61ATOM 1121 CB ALA 809 17.950 13.283 18.321 1.00 18.30ATOM 1122 C ALA 809 18.105 10.786 18.532 1.00 18.88ATOM 1123 O ALA 809 18.986 10.210 19.167 1.00 18.79ATOM 1124 N LEU 810 16.842 10.369 18.533 1.00 19.30ATOM 1125 CA LEU 810 16.432 9.204 19.321 1.00 19.68ATOM 1126 CB LEU 810 14.917 9.033 19.242 1.00 19.80ATOM 1127 CG LEU 810 14.250 8.133 20.290 1.00 21.07ATOM 1128 CD1 LEU 810 14.607 8.601 21.706 1.00 21.00ATOM 1129 CD2 LEU 810 12.736 8.168 20.094 1.00 20.91ATOM 1130 C LEU 810 17.137 7.924 18.837 1.00 19.90ATOM 1131 O LEU 810 17.497 7.051 19.631 1.00 19.94ATOM 1132 N LEU 811 17.347 7.824 17.530 1.00 20.06ATOM 1133 CA LEU 811 18.010 6.665 16.949 1.00 20.23ATOM 1134 CB LEU 811 18.125 6.825 15.424 1.00 19.95ATOM 1135 CG LEU 811 17.498 5.720 14.561 1.00 20.82ATOM 1136 CD1 LEU 811 17.661 6.059 13.079 1.00 20.39ATOM 1137 CD2 LEU 811 18.139 4.380 14.874 1.00 20.09ATOM 1138 C LEU 811 19.407 6.447 17.555 1.00 20.02ATOM 1139 O LEU 811 19.889 5.326 17.622 1.00 20.87ATOM 1140 N LEU 812 20.060 7.513 17.992 1.00 19.93ATOM 1141 CA LEU 812 21.389 7.380 18.581 1.00 19.94ATOM 1142 CB LEU 812 22.041 8.753 18.753 1.00 19.93ATOM 1143 CG LEU 812 23.309 8.740 19.607 1.00 19.48ATOM 1144 CD1 LEU 812 24.523 8.421 18.748 1.00 19.57ATOM 1145 CD2 LEU 812 23.467 10.068 20.272 1.00 19.85ATOM 1146 C LEU 812 21.355 6.692 19.940 1.00 19.79ATOM 1147 O LEU 812 22.383 6.237 20.414 1.00 19.89ATOM 1148 N PHE 813 20.182 6.638 20.564 1.00 20.27ATOM 1149 CA PHE 813 20.025 6.011 21.872 1.00 20.89ATOM 1150 CB PHE 813 19.334 6.988 22.830 1.00 21.71ATOM 1151 CG PHE 813 20.049 8.309 22.964 1.00 22.53ATOM 1152 CD1 PHE 813 21.296 8.381 23.575 1.00 22.94ATOM 1153 CD2 PHE 813 19.483 9.475 22.452 1.00 22.60ATOM 1154 CE1 PHE 813 21.974 9.600 23.676 1.00 23.67ATOM 1155 CE2 PHE 813 20.143 10.698 22.543 1.00 23.12ATOM 1156 CZ PHE 813 21.392 10.764 23.156 1.00 24.01ATOM 1157 C PHE 813 19.233 4.706 21.814 1.00 21.29ATOM 1158 O PHE 813 18.573 4.327 22.780 1.00 20.70ATOM 1159 N SER 814 19.304 4.013 20.680 1.00 22.24ATOM 1160 CA SER 814 18.571 2.762 20.526 1.00 22.82ATOM 1161 CB SER 814 17.604 2.870 19.352 1.00 23.27ATOM 1162 OG SER 814 16.529 3.731 19.689 1.00 25.04ATOM 1163 C SER 814 19.402 1.502 20.387 1.00 22.78ATOM 1164 O SER 814 18.901 0.486 19.933 1.00 23.31ATOM 1165 N ILE 815 20.664 1.554 20.792 1.00 23.17ATOM 1166 CA ILE 815 21.519 0.388 20.715 1.00 24.25ATOM 1167 CB ILE 815 22.260 0.339 19.361 1.00 25.14ATOM 1168 CG2 ILE 815 22.988 1.640 19.099 1.00 25.51ATOM 1169 CG1 ILE 815 23.222 -0.849 19.343 1.00 26.20ATOM 1170 CD1 ILE 815 22.524 -2.177 19.315 1.00 26.03ATOM 1171 C ILE 815 22.500 0.376 21.888 1.00 24.71ATOM 1172 O ILE 815 23.306 1.292 22.065 1.00 24.79ATOM 1173 N ILE 816 22.417 -0.671 22.700 1.00 25.36ATOM 1174 CA ILE 816 23.263 -0.784 23.887 1.00 26.22ATOM 1175 CB ILE 816 22.595 -0.092 25.081 1.00 25.90ATOM 1176 CG2 ILE 816 22.537 1.422 24.853 1.00 25.91ATOM 1177 CG1 ILE 816 21.202 -0.690 25.282 1.00 25.62ATOM 1178 CD1 ILE 816 20.460 -0.144 26.481 1.00 26.47ATOM 1179 C ILE 816 23.570 -2.220 24.328 1.00 26.59ATOM 1180 O ILE 816 22.807 -3.142 24.048 1.00 26.12ATOM 1181 N PRO 817 24.694 -2.413 25.041 1.00 27.17ATOM 1182 CD PRO 817 25.758 -1.427 25.304 1.00 27.29ATOM 1183 CA PRO 817 25.085 -3.742 25.525 1.00 27.80ATOM 1184 CB PRO 817 26.384 -3.474 26.284 1.00 27.15ATOM 1185 CG PRO 817 26.958 -2.313 25.557 1.00 27.61ATOM 1186 C PRO 817 24.010 -4.324 26.435 1.00 28.43ATOM 1187 O PRO 817 23.380 -3.600 27.212 1.00 27.45ATOM 1188 N VAL 818 23.808 -5.634 26.312 1.00 29.98ATOM 1189 CA VAL 818 22.833 -6.380 27.108 1.00 31.48ATOM 1190 CB VAL 818 22.947 -7.891 26.825 1.00 31.98ATOM 1191 CG1 VAL 818 24.335 -8.377 27.215 1.00 33.11ATOM 1192 CG2 VAL 818 21.879 -8.665 27.590 1.00 32.85ATOM 1193 C VAL 818 23.032 -6.163 28.609 1.00 32.15ATOM 1194 O VAL 818 22.069 -6.152 29.364 1.00 32.43ATOM 1195 N ASP 819 24.276 -5.997 29.046 1.00 33.13ATOM 1196 CA ASP 819 24.536 -5.786 30.466 1.00 34.13ATOM 1197 CB ASP 819 25.707 -6.662 30.932 1.00 35.28ATOM 1198 CG ASP 819 27.024 -6.302 30.258 1.00 36.52ATOM 1199 OD1 ASP 819 27.991 -7.091 30.403 1.00 37.48ATOM 1200 OD2 ASP 819 27.097 -5.242 29.591 1.00 37.03ATOM 1201 C ASP 819 24.798 -4.315 30.798 1.00 34.30ATOM 1202 O ASP 819 25.668 -3.989 31.610 1.00 33.84ATOM 1203 N GLY 820 24.026 -3.440 30.150 1.00 34.60ATOM 1204 CA GLY 820 24.125 -2.005 30.361 1.00 34.11ATOM 1205 C GLY 820 25.477 -1.375 30.121 1.00 33.97ATOM 1206 O GLY 820 26.474 -2.068 29.945 1.00 33.92ATOM 1207 N LEU 821 25.493 -0.042 30.133 1.00 34.32ATOM 1208 CA LEU 821 26.693 0.768 29.925 1.00 34.47ATOM 1209 CB LEU 821 26.330 2.053 29.191 1.00 34.92ATOM 1210 CG LEU 821 25.887 2.042 27.733 1.00 35.26ATOM 1211 CD1 LEU 821 25.251 3.398 27.420 1.00 35.53ATOM 1212 CD2 LEU 821 27.080 1.769 26.819 1.00 34.91ATOM 1213 C LEU 821 27.348 1.154 31.242 1.00 34.74ATOM 1214 O LEU 821 26.836 0.841 32.313 1.00 34.48ATOM 1215 N LYS 822 28.476 1.855 31.148 1.00 35.36ATOM 1216 CA LYS 822 29.211 2.316 32.325 1.00 36.27ATOM 1217 CB LYS 822 30.384 3.204 31.903 1.00 36.87ATOM 1218 CG LYS 822 31.286 2.590 30.856 1.00 37.44ATOM 1219 CD LYS 822 31.934 1.317 31.361 1.00 38.01ATOM 1220 CE LYS 822 32.921 0.770 30.343 1.00 38.61ATOM 1221 NZ LYS 822 34.065 1.699 30.117 1.00 39.07ATOM 1222 C LYS 822 28.296 3.112 33.263 1.00 36.51ATOM 1223 O LYS 822 28.440 3.056 34.480 1.00 36.71ATOM 1224 N ASN 823 27.359 3.859 32.690 1.00 36.69ATOM 1225 CA ASN 823 26.424 4.644 33.483 1.00 36.49ATOM 1226 CB ASN 823 26.893 6.098 33.529 1.00 37.62ATOM 1227 CG ASN 823 28.271 6.239 34.150 1.00 39.08ATOM 1228 OD1 ASN 823 29.251 5.668 33.658 1.00 39.96ATOM 1229 ND2 ASN 823 28.356 7.000 35.244 1.00 39.54ATOM 1230 C ASN 823 25.009 4.550 32.908 1.00 35.90ATOM 1231 O ASN 823 24.470 5.523 32.380 1.00 35.84ATOM 1232 N GLN 824 24.410 3.371 33.026 1.00 35.27ATOM 1233 CA GLN 824 23.064 3.128 32.512 1.00 34.89ATOM 1234 CB GLN 824 22.544 1.759 32.968 1.00 35.03ATOM 1235 CG GLN 824 22.418 0.736 31.853 1.00 35.35ATOM 1236 CD GLN 824 21.877 1.332 30.573 1.00 36.02ATOM 1237 OE1 GLN 824 20.725 1.789 30.507 1.00 36.30ATOM 1238 NE2 GLN 824 22.713 1.341 29.538 1.00 36.24ATOM 1239 C GLN 824 22.016 4.159 32.879 1.00 34.22ATOM 1240 O GLN 824 21.240 4.589 32.029 1.00 34.41ATOM 1241 N LYS 825 21.980 4.534 34.150 1.00 33.69ATOM 1242 CA LYS 825 20.989 5.478 34.645 1.00 33.20ATOM 1243 CB LYS 825 21.240 5.765 36.120 1.00 33.85ATOM 1244 CG LYS 825 20.044 6.323 36.860 1.00 34.71ATOM 1245 CD LYS 825 18.931 5.304 36.990 1.00 35.57ATOM 1246 CE LYS 825 17.744 5.903 37.732 1.00 36.43ATOM 1247 NZ LYS 825 18.151 6.447 39.063 1.00 37.01ATOM 1248 C LYS 825 20.929 6.788 33.870 1.00 32.38ATOM 1249 O LYS 825 19.857 7.329 33.656 1.00 32.60ATOM 1250 N PHE 826 22.077 7.299 33.453 1.00 31.31ATOM 1251 CA PHE 826 22.094 8.543 32.709 1.00 30.15ATOM 1252 CB PHE 826 23.496 9.152 32.709 1.00 30.44ATOM 1253 CG PHE 826 24.003 9.506 34.076 1.00 31.16ATOM 1254 CD1 PHE 826 25.088 10.364 34.226 1.00 32.02ATOM 1255 CD2 PHE 826 23.415 8.973 35.219 1.00 31.65ATOM 1256 CE1 PHE 826 25.579 10.682 35.496 1.00 31.86ATOM 1257 CE2 PHE 826 23.900 9.285 36.490 1.00 31.49ATOM 1258 CZ PHE 826 24.983 10.140 36.624 1.00 31.58ATOM 1259 C PHE 826 21.618 8.307 31.283 1.00 28.87ATOM 1260 O PHE 826 20.921 9.142 30.720 1.00 28.43ATOM 1261 N PHE 827 21.989 7.166 30.708 1.00 27.44ATOM 1262 CA PHE 827 21.568 6.833 29.354 1.00 26.53ATOM 1263 CB PHE 827 22.122 5.476 28.935 1.00 25.44ATOM 1264 CG PHE 827 21.708 5.061 27.556 1.00 24.15ATOM 1265 CD1 PHE 827 22.592 5.157 26.493 1.00 23.63ATOM 1266 CD2 PHE 827 20.425 4.599 27.312 1.00 23.97ATOM 1267 CE1 PHE 827 22.202 4.800 25.203 1.00 23.50ATOM 1268 CE2 PHE 827 20.026 4.241 26.016 1.00 23.68ATOM 1269 CZ PHE 827 20.913 4.342 24.968 1.00 22.72ATOM 1270 C PHE 827 20.045 6.788 29.340 1.00 26.44ATOM 1271 O PHE 827 19.406 7.407 28.492 1.00 26.04ATOM 1272 N ASP 828 19.475 6.052 30.296 1.00 26.33ATOM 1273 CA ASP 828 18.022 5.931 30.436 1.00 26.22ATOM 1274 CB ASP 828 17.669 5.082 31.654 1.00 27.34ATOM 1275 CG ASP 828 18.195 3.673 31.567 1.00 28.47ATOM 1276 OD1 ASP 828 18.511 3.119 32.644 1.00 29.17ATOM 1277 OD2 ASP 828 18.281 3.117 30.448 1.00 28.69ATOM 1278 C ASP 828 17.332 7.288 30.601 1.00 25.75ATOM 1279 O ASP 828 16.266 7.506 30.052 1.00 25.47ATOM 1280 N GLU 829 17.915 8.191 31.382 1.00 25.59ATOM 1281 CA GLU 829 17.292 9.494 31.559 1.00 26.44ATOM 1282 CB GLU 829 18.006 10.303 32.650 1.00 28.25ATOM 1283 CG GLU 829 17.415 11.696 32.898 1.00 30.25ATOM 1284 CD GLU 829 18.210 12.499 33.925 1.00 32.25ATOM 1285 OE1 GLU 829 19.432 12.719 33.717 1.00 33.52ATOM 1286 OE2 GLU 829 17.618 12.918 34.946 1.00 33.33ATOM 1287 C GLU 829 17.343 10.233 30.223 1.00 25.94ATOM 1288 O GLU 829 16.342 10.797 29.777 1.00 25.19ATOM 1289 N LEU 830 18.506 10.208 29.575 1.00 25.30ATOM 1290 CA LEU 830 18.645 10.859 28.282 1.00 25.23ATOM 1291 CB LEU 830 20.072 10.736 27.761 1.00 26.02ATOM 1292 CG LEU 830 20.940 11.959 28.038 1.00 27.07ATOM 1293 CD1 LEU 830 21.096 12.139 29.555 1.00 28.25ATOM 1294 CD2 LEU 830 22.298 11.793 27.362 1.00 27.32ATOM 1295 C LEU 830 17.678 10.249 27.279 1.00 25.12ATOM 1296 O LEU 830 16.943 10.966 26.606 1.00 24.67ATOM 1297 N ARG 831 17.668 8.922 27.188 1.00 25.07ATOM 1298 CA ARG 831 16.768 8.253 26.261 1.00 25.48ATOM 1299 CB ARG 831 16.913 6.732 26.358 1.00 25.48ATOM 1300 CG ARG 831 15.953 5.993 25.441 1.00 25.24ATOM 1301 CD ARG 831 16.261 4.499 25.357 1.00 25.58ATOM 1302 NE ARG 831 15.158 3.781 24.719 1.00 25.78ATOM 1303 CZ ARG 831 14.822 3.879 23.436 1.00 25.10ATOM 1304 NH1 ARG 831 15.507 4.661 22.617 1.00 24.95ATOM 1305 NH2 ARG 831 13.774 3.213 22.982 1.00 25.49ATOM 1306 C ARG 831 15.319 8.654 26.526 1.00 25.51ATOM 1307 O ARG 831 14.559 8.929 25.590 1.00 25.14ATOM 1308 N MET 832 14.948 8.697 27.804 1.00 25.71ATOM 1309 CA MET 832 13.591 9.070 28.202 1.00 26.13ATOM 1310 CB MET 832 13.393 8.855 29.706 1.00 26.07ATOM 1311 CG MET 832 12.280 9.683 30.316 1.00 25.80ATOM 1312 SD MET 832 11.876 9.192 32.002 1.00 28.43ATOM 1313 CE MET 832 12.867 10.272 32.995 1.00 26.55ATOM 1314 C MET 832 13.255 10.518 27.847 1.00 25.99ATOM 1315 O MET 832 12.114 10.828 27.518 1.00 26.12ATOM 1316 N ASN 833 14.241 11.403 27.916 1.00 26.07ATOM 1317 CA ASN 833 13.996 12.800 27.590 1.00 26.18ATOM 1318 CB ASN 833 15.129 13.668 28.126 1.00 26.83ATOM 1319 CG ASN 833 15.026 13.874 29.625 1.00 27.86ATOM 1320 OD1 ASN 833 16.004 14.206 30.297 1.00 28.97ATOM 1321 ND2 ASN 833 13.827 13.682 30.156 1.00 27.93ATOM 1322 C ASN 833 13.795 13.021 26.099 1.00 26.03ATOM 1323 O ASN 833 12.989 13.856 25.701 1.00 25.96ATOM 1324 N TYR 834 14.513 12.267 25.277 1.00 25.89ATOM 1325 CA TYR 834 14.375 12.385 23.835 1.00 26.53ATOM 1326 CB TYR 834 15.572 11.732 23.142 1.00 25.95ATOM 1327 CG TYR 834 16.759 12.670 23.114 1.00 25.75ATOM 1328 CD1 TYR 834 17.008 13.471 22.004 1.00 25.23ATOM 1329 CE1 TYR 834 18.028 14.418 22.017 1.00 25.38ATOM 1330 CD2 TYR 834 17.566 12.839 24.239 1.00 25.31ATOM 1331 CE2 TYR 834 18.584 13.784 24.260 1.00 24.66ATOM 1332 CZ TYR 834 18.813 14.569 23.149 1.00 24.63ATOM 1333 OH TYR 834 19.831 15.496 23.153 1.00 24.47ATOM 1334 C TYR 834 13.054 11.784 23.364 1.00 27.63ATOM 1335 O TYR 834 12.385 12.338 22.493 1.00 27.51ATOM 1336 N ILE 835 12.668 10.655 23.948 1.00 28.57ATOM 1337 CA ILE 835 11.404 10.044 23.586 1.00 29.73ATOM 1338 CB ILE 835 11.131 8.765 24.404 1.00 29.44ATOM 1339 CG2 ILE 835 9.640 8.458 24.415 1.00 29.00ATOM 1340 CG1 ILE 835 11.940 7.598 23.828 1.00 29.23ATOM 1341 CD1 ILE 835 11.798 6.295 24.604 1.00 28.37ATOM 1342 C ILE 835 10.294 11.053 23.861 1.00 31.03ATOM 1343 O ILE 835 9.354 11.171 23.084 1.00 30.89ATOM 1344 N LYS 836 10.410 11.777 24.971 1.00 32.73ATOM 1345 CA LYS 836 9.411 12.772 25.335 1.00 34.47ATOM 1346 CB LYS 836 9.613 13.246 26.781 1.00 35.12ATOM 1347 CG LYS 836 9.220 12.210 27.845 1.00 36.26ATOM 1348 CD LYS 836 9.047 12.853 29.226 1.00 36.96ATOM 1349 CE LYS 836 8.689 11.822 30.292 1.00 37.93ATOM 1350 NZ LYS 836 7.331 11.205 30.106 1.00 38.44ATOM 1351 C LYS 836 9.411 13.974 24.401 1.00 35.36ATOM 1352 O LYS 836 8.401 14.663 24.288 1.00 35.57ATOM 1353 N GLU 837 10.533 14.232 23.730 1.00 36.74ATOM 1354 CA GLU 837 10.605 15.360 22.801 1.00 37.88ATOM 1355 CB GLU 837 12.056 15.750 22.516 1.00 38.02ATOM 1356 CG GLU 837 12.811 16.300 23.720 1.00 38.61ATOM 1357 CD GLU 837 12.171 17.552 24.298 1.00 38.88ATOM 1358 OE1 GLU 837 12.694 18.080 25.301 1.00 38.97ATOM 1359 OE2 GLU 837 11.145 18.011 23.751 1.00 39.85ATOM 1360 C GLU 837 9.902 14.995 21.502 1.00 39.04ATOM 1361 O GLU 837 9.248 15.837 20.883 1.00 39.39ATOM 1362 N LEU 838 10.035 13.737 21.089 1.00 40.19ATOM 1363 CA LEU 838 9.377 13.283 19.873 1.00 41.66ATOM 1364 CB LEU 838 9.745 11.840 19.551 1.00 40.92ATOM 1365 CG LEU 838 9.059 11.325 18.283 1.00 40.71ATOM 1366 CD1 LEU 838 9.337 12.287 17.131 1.00 40.13ATOM 1367 CD2 LEU 838 9.549 9.921 17.961 1.00 40.28ATOM 1368 C LEU 838 7.882 13.376 20.098 1.00 43.18ATOM 1369 O LEU 838 7.117 13.684 19.187 1.00 43.33ATOM 1370 N ASP 839 7.469 13.105 21.329 1.00 45.15ATOM 1371 CA ASP 839 6.063 13.176 21.679 1.00 47.48ATOM 1372 CB ASP 839 5.852 12.690 23.109 1.00 47.71ATOM 1373 CG ASP 839 4.409 12.777 23.538 1.00 48.24ATOM 1374 OD1 ASP 839 3.575 12.016 22.996 1.00 48.44ATOM 1375 OD2 ASP 839 4.108 13.617 24.411 1.00 48.69ATOM 1376 C ASP 839 5.565 14.617 21.539 1.00 48.74ATOM 1377 O ASP 839 4.525 14.866 20.938 1.00 48.83ATOM 1378 N ARG 840 6.314 15.566 22.086 1.00 50.51ATOM 1379 CA ARG 840 5.922 16.965 21.999 1.00 52.38ATOM 1380 CB ARG 840 6.739 17.805 22.985 1.00 52.53ATOM 1381 CG ARG 840 6.330 17.586 24.444 1.00 53.33ATOM 1382 CD ARG 840 7.033 18.548 25.395 1.00 53.67ATOM 1383 NE ARG 840 8.378 18.110 25.759 1.00 53.99ATOM 1384 CZ ARG 840 9.318 18.922 26.232 1.00 54.20ATOM 1385 NH1 ARG 840 9.057 20.214 26.388 1.00 54.27ATOM 1386 NH2 ARG 840 10.513 18.447 26.558 1.00 54.13ATOM 1387 C ARG 840 6.041 17.534 20.585 1.00 53.55ATOM 1388 O ARG 840 5.293 18.436 20.211 1.00 53.71ATOM 1389 N ILE 841 6.979 17.021 19.796 1.00 54.98ATOM 1390 CA ILE 841 7.120 17.511 18.433 1.00 56.52ATOM 1391 CB ILE 841 8.440 17.040 17.784 1.00 56.31ATOM 1392 CG2 ILE 841 8.442 15.540 17.629 1.00 56.61ATOM 1393 CG1 ILE 841 8.600 17.678 16.405 1.00 56.35ATOM 1394 CD1 ILE 841 8.600 19.187 16.425 1.00 56.59ATOM 1395 C ILE 841 5.927 16.955 17.659 1.00 57.71ATOM 1396 O ILE 841 5.593 17.414 16.564 1.00 57.95ATOM 1397 N ILE 842 5.285 15.955 18.247 1.00 59.05ATOM 1398 CA ILE 842 4.115 15.345 17.644 1.00 60.55ATOM 1399 CB ILE 842 3.929 13.899 18.145 1.00 60.34ATOM 1400 CG2 ILE 842 2.539 13.386 17.786 1.00 60.36ATOM 1401 CG1 ILE 842 5.014 13.002 17.552 1.00 60.28ATOM 1402 CD1 ILE 842 4.968 12.899 16.046 1.00 60.36ATOM 1403 C ILE 842 2.886 16.173 18.021 1.00 61.84ATOM 1404 O ILE 842 2.077 16.521 17.165 1.00 62.01ATOM 1405 N ALA 843 2.768 16.503 19.304 1.00 63.28ATOM 1406 CA ALA 843 1.636 17.274 19.811 1.00 64.93ATOM 1407 CB ALA 843 1.202 16.719 21.168 1.00 64.96ATOM 1408 C ALA 843 1.921 18.770 19.931 1.00 66.08ATOM 1409 O ALA 843 2.657 19.346 19.125 1.00 66.22ATOM 1410 N CYS 844 1.327 19.393 20.946 1.00 67.46ATOM 1411 CA CYS 844 1.499 20.825 21.187 1.00 68.93ATOM 1412 CB CYS 844 0.818 21.235 22.496 1.00 69.02ATOM 1413 SG CYS 844 1.052 22.983 22.913 1.00 69.96ATOM 1414 C CYS 844 2.965 21.264 21.224 1.00 69.69ATOM 1415 O CYS 844 3.734 20.858 22.103 1.00 69.75ATOM 1416 N ALA 845 3.331 22.104 20.260 1.00 70.51ATOM 1417 CA ALA 845 4.685 22.631 20.138 1.00 71.20ATOM 1418 CB ALA 845 5.697 21.488 20.150 1.00 71.12ATOM 1419 C ALA 845 4.805 23.418 18.837 1.00 71.67ATOM 1420 O ALA 845 5.173 24.599 18.838 1.00 71.61ATOM 1421 N ALA 846 4.473 22.754 17.732 1.00 72.18ATOM 1422 CA ALA 846 4.555 23.359 16.411 1.00 72.76ATOM 1423 CB ALA 846 5.743 22.785 15.670 1.00 72.64ATOM 1424 C ALA 846 3.291 23.178 15.572 1.00 73.29ATOM 1425 O ALA 846 2.639 24.157 15.204 1.00 73.45ATOM 1426 N LYS 847 2.949 21.925 15.273 1.00 73.74ATOM 1427 CA LYS 847 1.780 21.617 14.450 1.00 74.06ATOM 1428 CB LYS 847 1.558 20.100 14.383 1.00 74.11ATOM 1429 CG LYS 847 2.498 19.384 13.412 1.00 74.21ATOM 1430 CD LYS 847 2.359 19.953 12.002 1.00 74.15ATOM 1431 CE LYS 847 3.331 19.313 11.026 1.00 74.04ATOM 1432 NZ LYS 847 3.206 19.907 9.662 1.00 73.48ATOM 1433 C LYS 847 0.478 22.307 14.842 1.00 74.24ATOM 1434 O LYS 847 0.203 22.539 16.021 1.00 74.15ATOM 1435 N ALA 848 -0.311 22.632 13.820 1.00 74.54ATOM 1436 CA ALA 848 -1.600 23.296 13.981 1.00 74.71ATOM 1437 CB ALA 848 -1.786 24.350 12.885 1.00 74.65ATOM 1438 C ALA 848 -2.755 22.289 13.948 1.00 74.78ATOM 1439 O ALA 848 -3.691 22.386 14.746 1.00 75.01ATOM 1440 N PRO 849 -2.715 21.318 13.016 1.00 74.70ATOM 1441 CD PRO 849 -1.791 21.178 11.874 1.00 74.87ATOM 1442 CA PRO 849 -3.789 20.320 12.936 1.00 74.53ATOM 1443 CB PRO 849 -3.627 19.756 11.529 1.00 74.63ATOM 1444 CG PRO 849 -2.143 19.803 11.336 1.00 74.79ATOM 1445 C PRO 849 -3.632 19.250 14.014 1.00 74.18ATOM 1446 O PRO 849 -2.519 18.800 14.286 1.00 74.25ATOM 1447 N THR 850 -4.746 18.848 14.621 1.00 73.78ATOM 1448 CA THR 850 -4.736 17.840 15.682 1.00 73.31ATOM 1449 CB THR 850 -6.180 17.441 16.067 1.00 73.45ATOM 1450 OG1 THR 850 -6.144 16.387 17.038 1.00 73.57ATOM 1451 CG2 THR 850 -6.961 16.990 14.832 1.00 73.61ATOM 1452 C THR 850 -3.933 16.578 15.329 1.00 72.80ATOM 1453 O THR 850 -4.467 15.613 14.771 1.00 72.81ATOM 1454 N SER 851 -2.648 16.591 15.675 1.00 71.96ATOM 1455 CA SER 851 -1.751 15.471 15.393 1.00 71.07ATOM 1456 CB SER 851 -0.664 15.924 14.405 1.00 71.04ATOM 1457 OG SER 851 0.243 14.881 14.097 1.00 70.59ATOM 1458 C SER 851 -1.099 14.932 16.670 1.00 70.34ATOM 1459 O SER 851 -0.015 15.370 17.047 1.00 70.40ATOM 1460 N CYS 852 -1.759 13.982 17.333 1.00 69.35ATOM 1461 CA CYS 852 -1.225 13.395 18.565 1.00 68.12ATOM 1462 CB CYS 852 -1.375 14.384 19.735 1.00 68.59ATOM 1463 SG CYS 852 -3.043 15.096 19.978 1.00 69.59ATOM 1464 C CYS 852 -1.854 12.050 18.944 1.00 66.82ATOM 1465 O CYS 852 -1.848 11.662 20.113 1.00 66.81ATOM 1466 N SER 853 -2.382 11.334 17.956 1.00 65.27ATOM 1467 CA SER 853 -3.007 10.041 18.211 1.00 63.60ATOM 1468 CB SER 853 -4.373 9.970 17.514 1.00 63.93ATOM 1469 OG SER 853 -4.272 10.324 16.148 1.00 63.97ATOM 1470 C SER 853 -2.134 8.862 17.778 1.00 62.15ATOM 1471 O SER 853 -1.316 8.371 18.562 1.00 62.22ATOM 1472 N ARG 854 -2.305 8.411 16.537 1.00 60.15ATOM 1473 CA ARG 854 -1.532 7.282 16.021 1.00 58.00ATOM 1474 CB ARG 854 -2.376 6.455 15.035 1.00 58.75ATOM 1475 CG ARG 854 -2.622 7.112 13.680 1.00 59.49ATOM 1476 CD ARG 854 -3.460 6.203 12.778 1.00 60.59ATOM 1477 NE ARG 854 -3.671 6.744 11.429 1.00 61.32ATOM 1478 CZ ARG 854 -4.324 7.873 11.150 1.00 61.65ATOM 1479 NH1 ARG 854 -4.848 8.611 12.124 1.00 61.58ATOM 1480 NH2 ARG 854 -4.454 8.267 9.887 1.00 61.67ATOM 1481 C ARG 854 -0.241 7.730 15.339 1.00 55.94ATOM 1482 O ARG 854 0.411 6.952 14.653 1.00 55.60ATOM 1483 N ARG 855 0.129 8.987 15.540 1.00 53.73ATOM 1484 CA ARG 855 1.342 9.528 14.946 1.00 51.51ATOM 1485 CB ARG 855 1.337 11.051 15.063 1.00 50.74ATOM 1486 CG ARG 855 2.404 11.739 14.247 1.00 49.65ATOM 1487 CD ARG 855 2.238 11.446 12.760 1.00 48.66ATOM 1488 NE ARG 855 3.212 12.183 11.966 1.00 46.95ATOM 1489 CZ ARG 855 3.327 12.088 10.650 1.00 46.55ATOM 1490 NH1 ARG 855 2.526 11.280 9.967 1.00 45.80ATOM 1491 NH2 ARG 855 4.248 12.802 10.020 1.00 46.32ATOM 1492 C ARG 855 2.580 8.955 15.642 1.00 50.40ATOM 1493 O ARG 855 3.633 8.777 15.026 1.00 50.15ATOM 1494 N PHE 856 2.448 8.669 16.933 1.00 48.68ATOM 1495 CA PHE 856 3.554 8.117 17.694 1.00 46.90ATOM 1496 CB PHE 856 3.327 8.325 19.196 1.00 47.21ATOM 1497 CG PHE 856 4.461 7.836 20.058 1.00 47.24ATOM 1498 CD1 PHE 856 5.710 8.448 20.004 1.00 47.28ATOM 1499 CD2 PHE 856 4.278 6.766 20.930 1.00 47.12ATOM 1500 CE1 PHE 856 6.761 8.000 20.811 1.00 47.48ATOM 1501 CE2 PHE 856 5.324 6.312 21.743 1.00 47.30ATOM 1502 CZ PHE 856 6.566 6.929 21.684 1.00 47.08ATOM 1503 C PHE 856 3.705 6.633 17.393 1.00 45.50ATOM 1504 O PHE 856 4.825 6.122 17.331 1.00 45.41ATOM 1505 N TYR 857 2.584 5.940 17.196 1.00 43.60ATOM 1506 CA TYR 857 2.643 4.511 16.910 1.00 41.70ATOM 1507 CB TYR 857 1.249 3.880 16.893 1.00 42.01ATOM 1508 CG TYR 857 1.271 2.393 16.574 1.00 42.12ATOM 1509 CD1 TYR 857 1.713 1.462 17.512 1.00 42.35ATOM 1510 CE1 TYR 857 1.785 0.100 17.206 1.00 42.40ATOM 1511 CD2 TYR 857 0.895 1.923 15.315 1.00 42.37ATOM 1512 CE2 TYR 857 0.967 0.562 14.997 1.00 42.18ATOM 1513 CZ TYR 857 1.414 -0.341 15.946 1.00 42.56ATOM 1514 OH TYR 857 1.516 -1.681 15.629 1.00 42.93ATOM 1515 C TYR 857 3.323 4.222 15.582 1.00 40.32ATOM 1516 O TYR 857 4.092 3.266 15.478 1.00 40.51ATOM 1517 N GLN 858 3.047 5.023 14.558 1.00 38.44ATOM 1518 CA GLN 858 3.682 4.764 13.271 1.00 36.90ATOM 1519 CB GLN 858 2.888 5.372 12.104 1.00 37.28ATOM 1520 CG GLN 858 2.188 6.677 12.379 1.00 37.76ATOM 1521 CD GLN 858 0.934 6.820 11.536 1.00 38.54ATOM 1522 OE1 GLN 858 0.165 5.862 11.391 1.00 38.69ATOM 1523 NE2 GLN 858 0.712 8.012 10.982 1.00 38.73ATOM 1524 C GLN 858 5.134 5.201 13.210 1.00 35.37ATOM 1525 O GLN 858 5.949 4.501 12.612 1.00 35.14ATOM 1526 N LEU 859 5.471 6.330 13.834 1.00 33.65ATOM 1527 CA LEU 859 6.859 6.782 13.826 1.00 32.33ATOM 1528 CB LEU 859 6.995 8.191 14.412 1.00 32.33ATOM 1529 CG LEU 859 6.425 9.362 13.596 1.00 32.70ATOM 1530 CD1 LEU 859 6.736 10.688 14.294 1.00 32.82ATOM 1531 CD2 LEU 859 7.017 9.368 12.210 1.00 32.87ATOM 1532 C LEU 859 7.743 5.806 14.607 1.00 31.28ATOM 1533 O LEU 859 8.844 5.475 14.174 1.00 30.56ATOM 1534 N THR 860 7.264 5.339 15.754 1.00 30.60ATOM 1535 CA THR 860 8.043 4.389 16.550 1.00 30.04ATOM 1536 CB THR 860 7.398 4.142 17.938 1.00 30.12ATOM 1537 OG1 THA 860 6.024 3.776 17.777 1.00 30.74ATOM 1538 CG2 THR 860 7.472 5.403 18.780 1.00 29.71ATOM 1539 C THR 860 8.162 3.083 15.764 1.00 29.10ATOM 1540 O THR 860 9.114 2.329 15.926 1.00 28.88ATOM 1541 N LYS 861 7.191 2.839 14.893 1.00 28.36ATOM 1542 CA LYS 861 7.202 1.659 14.039 1.00 27.61ATOM 1543 CB LYS 861 5.855 1.517 13.334 1.00 28.44ATOM 1544 CG LYS 861 5.025 0.365 13.819 1.00 29.58ATOM 1545 CD LYS 861 5.650 -0.948 13.420 1.00 30.16ATOM 1546 CE LYS 861 4.869 -2.106 13.998 1.00 30.39ATOM 1547 NZ LYS 861 5.567 -3.402 13.771 1.00 31.31ATOM 1548 C LYS 861 8.291 1.885 12.991 1.00 26.55ATOM 1549 O LYS 861 9.097 1.002 12.680 1.00 26.06ATOM 1550 N LEU 862 8.300 3.088 12.439 1.00 25.35ATOM 1551 CA LEU 862 9.288 3.421 11.439 1.00 24.93ATOM 1552 CB LEU 862 9.030 4.818 10.891 1.00 24.31ATOM 1553 CG LEU 862 10.060 5.242 9.855 1.00 24.36ATOM 1554 CD1 LEU 862 9.948 4.337 8.645 1.00 23.62ATOM 1555 CD2 LEU 862 9.846 6.687 9.484 1.00 23.25ATOM 1556 C LEU 862 10.692 3.332 12.038 1.00 24.54ATOM 1557 0 LEU 862 11.581 2.748 11.433 1.00 24.21ATOM 1558 N LEU 863 10.894 3.901 13.227 1.00 24.64ATOM 1559 CA LEU 863 12.216 3.843 13.868 1.00 24.87ATOM 1560 CB LEU 863 12.216 4.613 15.188 1.00 24.73ATOM 1561 CG LEU 863 12.307 6.129 15.049 1.00 25.00ATOM 1562 CD1 LEU 863 12.356 6.762 16.428 1.00 24.84ATOM 1563 CD2 LEU 863 13.554 6.483 14.240 1.00 25.12ATOM 1564 C LEU 863 12.689 2.402 14.105 1.00 24.37ATOM 1565 O LEU 863 13.837 2.068 13.826 1.00 24.46ATOM 1566 N ASP 864 11.815 1.549 14.622 1.00 24.20ATOM 1567 CA ASP 864 12.190 0.154 14.835 1.00 24.33ATOM 1568 CB ASP 864 11.014 -0.626 15.438 1.00 25.03ATOM 1569 CG ASP 864 10.670 -0.189 16.878 1.00 26.02ATOM 1570 OD1 ASP 864 11.490 0.519 17.518 1.00 25.80ATOM 1571 OD2 ASP 864 9.578 -0.573 17.367 1.00 25.23ATOM 1572 C ASP 864 12.598 -0.511 13.499 1.00 24.21ATOM 1573 O ASP 864 13.473 -1.383 13.460 1.00 24.29ATOM 1574 N SER 865 11.966 -0.090 12.404 1.00 23.73ATOM 1575 CA SER 865 12.237 -0.682 11.098 1.00 23.19ATOM 1576 CB SER 865 11.217 -0.194 10.052 1.00 22.65ATOM 1577 OG SER 865 11.527 1.099 9.565 1.00 21.98ATOM 1578 C SER 865 13.659 -0.432 10.611 1.00 23.12ATOM 1579 O SER 865 14.149 -1.138 9.738 1.00 23.62ATOM 1580 N VAL 866 14.331 0.562 11.178 1.00 22.48ATOM 1581 CA VAL 866 15.708 0.839 10.786 1.00 21.73ATOM 1582 CB VAL 866 16.190 2.188 11.345 1.00 20.85ATOM 1583 CG1 VAL 866 17.665 2.377 11.012 1.00 20.74ATOM 1584 CG2 VAL 866 15.354 3.317 10.784 1.00 19.44ATOM 1585 C VAL 866 16.653 -0.236 11.338 1.00 21.81ATOM 1586 O VAL 866 17.656 -0.598 10.723 1.00 22.06ATOM 1587 N GLN 867 16.327 -0.744 12.512 1.00 21.74ATOM 1588 CA GLN 867 17.178 -1.722 13.153 1.00 21.73ATOM 1589 CB GLN 867 16.607 -2.055 14.527 1.00 22.18ATOM 1590 CG GLN 867 16.498 -0.829 15.412 1.00 22.59ATOM 1591 CD GLN 867 17.837 -0.158 15.638 1.00 22.57ATOM 1592 OE1 GLN 867 18.826 -0.819 15.953 1.00 23.51ATOM 1593 NE2 GLN 867 17.873 1.158 15.497 1.00 22.55ATOM 1594 C GLN 867 17.481 -2.994 12.372 1.00 21.37ATOM 1595 O GLN 867 18.650 -3.330 12.187 1.00 21.44ATOM 1596 N PRO 868 16.448 -3.733 11.923 1.00 21.04ATOM 1597 CD PRO 868 14.989 -3.550 12.037 1.00 21.82ATOM 1598 CA PRO 868 16.770 -4.948 11.175 1.00 20.68ATOM 1599 CB PRO 868 15.390 -5.545 10.841 1.00 20.96ATOM 1600 CG PRO 868 14.468 -4.383 10.884 1.00 21.59ATOM 1601 C PRO 868 17.617 -4.622 9.950 1.00 20.19ATOM 1602 O PRO 868 18.479 -5.403 9.551 1.00 20.47ATOM 1603 N ILE 869 17.383 -3.455 9.362 1.00 19.77ATOM 1604 CA ILE 869 18.175 -3.037 8.216 1.00 18.93ATOM 1605 CB ILE 869 17.656 -1.698 7.649 1.00 18.67ATOM 1606 CG2 ITE 869 18.605 -1.185 6.545 1.00 18.45ATOM 1607 CG1 ILE 869 16.235 -1.890 7.121 1.00 18.20ATOM 1608 CD1 ILE 869 15.597 -0.642 6.543 1.00 17.92ATOM 1609 C ILE 869 19.641 -2.881 8.665 1.00 18.84ATOM 1610 O ILE 869 20.551 -3.408 8.023 1.00 17.81ATOM 1611 N ALA 870 19.863 -2.169 9.773 1.00 18.50ATOM 1612 CA ALA 870 21.221 -1.964 10.280 1.00 19.01ATOM 1613 CB ALA 870 21.207 -1.118 11.563 1.00 17.32ATOM 1614 C ALA 870 21.898 -3.305 10.541 1.00 19.42ATOM 1615 O ALA 870 23.104 -3.452 10.329 1.00 19.55ATOM 1616 N ARG 871 21.116 -4.286 10.981 1.00 20.41ATOM 1617 CA ARG 871 21.654 -5.615 11.274 1.00 21.54ATOM 1618 CB ARG 871 20.619 -6.462 12.038 1.00 21.89ATOM 1619 CG ARG 871 21.042 -7.895 12.307 1.00 23.32ATOM 1620 CD ARG 871 22.427 -7.959 12.926 1.00 25.37ATOM 1621 NE ARG 871 22.888 -9.331 13.146 1.00 26.95ATOM 1622 CZ ARG 871 22.292 -10.205 13.953 1.00 26.98ATOM 1623 NH1 ARG 871 21.202 -9.854 14.617 1.00 27.28ATOM 1624 NH2 ARG 871 22.803 -11.420 14.116 1.00 26.87ATOM 1625 C ARG 871 22.096 -6.316 9.992 1.00 22.03ATOM 1626 O ARG 871 23.135 -6.976 9.970 1.00 22.91ATOM 1627 N GLU 872 21.316 -6.171 8.922 1.00 21.94ATOM 1628 CA GLU 872 21.683 -6.772 7.647 1.00 21.84ATOM 1629 CB GLU 872 20.613 -6.515 6.578 1.00 23.42ATOM 1630 CG GLU 872 19.305 -7.281 6.758 1.00 25.54ATOM 1631 CD GLU 872 18.418 -7.213 5.518 1.00 27.28ATOM 1632 OE1 GLU 872 17.294 -7.766 5.553 1.00 28.13ATOM 1633 OE2 GLU 872 18.845 -6.612 4.503 1.00 27.83ATOM 1634 C GLU 872 23.005 -6.198 7.161 1.00 21.22ATOM 1635 O GLU 872 23.888 -6.941 6.742 1.00 21.80ATOM 1636 N LEU 873 23.140 -4.873 7.222 1.00 20.38ATOM 1637 CA LEU 873 24.353 -4.198 6.773 1.00 19.25ATOM 1638 CB LEU 873 24.115 -2.677 6.674 1.00 19.83ATOM 1639 CG LEU 873 23.051 -2.181 5.675 1.00 19.60ATOM 1640 CD1 LEU 873 23.053 -0.665 5.635 1.00 20.16ATOM 1641 CD2 LEU 873 23.330 -2.726 4.279 1.00 19.48ATOM 1642 C LEU 873 25.530 -4.489 7.690 1.00 19.03ATOM 1643 O LEU 873 26.670 -4.505 7.252 1.00 18.60ATOM 1644 N HIS 874 25.264 -4.720 8.972 1.00 18.94ATOM 1645 CA HIS 874 26.354 -5.037 9.880 1.00 18.94ATOM 1646 CB HIS 874 25.881 -5.078 11.337 1.00 18.69ATOM 1647 CG HIS 874 25.715 -3.729 11.956 1.00 17.78ATOM 1648 CD2 HIS 874 26.460 -2.605 11.855 1.00 17.59ATOM 1649 ND1 HIS 874 24.703 -3.440 12.843 1.00 17.53ATOM 1650 CE1 HIS 874 24.835 -2.196 13.267 1.00 17.42ATOM 1651 NE2 HIS 874 25.894 -1.667 12.685 1.00 17.13ATOM 1652 C HIS 874 26.879 -6.396 9.482 1.00 18.68ATOM 1653 O HIS 874 28.084 -6.611 9.418 1.00 18.92ATOM 1654 N GLN 875 25.971 -7.313 9.202 1.00 19.13ATOM 1655 CA GLN 875 26.374 -8.654 8.810 1.00 20.22ATOM 1656 CB GLN 875 25.141 -9.518 8.582 1.00 20.38ATOM 1657 CG GLN 875 25.441 -10.988 8.502 1.00 21.65ATOM 1658 CD GLN 875 26.165 -11.480 9.742 1.00 21.80ATOM 1659 OE1 GLN 875 27.387 -11.562 9.765 1.00 22.35ATOM 1660 NE2 GLN 875 25.40 -11.787 10.786 1.00 21.86ATOM 1661 C GLN 875 27.226 -8.609 7.536 1.00 20.68ATOM 1662 O GLN 875 28.321 -9.185 7.475 1.00 20.84ATOM 1663 N PHE 876 26.728 -7.904 6.527 1.00 21.33ATOM 1664 CA PHE 876 27.432 -7.778 5.257 1.00 21.58ATOM 1665 CB PHE 876 26.563 -7.003 4.258 1.00 22.76ATOM 1666 CG PHE 876 27.324 -6.426 3.099 1.00 23.48ATOM 1667 CD1 PHE 876 27.981 -5.211 3.220 1.00 24.12ATOM 1668 CD2 PHE 876 27.354 -7.084 1.876 1.00 24.70ATOM 1669 CE1 PHE 876 28.658 -4.646 2.139 1.00 25.07ATOM 1670 CE2 PHE 876 28.028 -6.535 0.780 1.00 25.33ATOM 1671 CZ PHE 876 28.684 -5.305 0.913 1.00 25.56ATOM 1672 C PHE 876 28.782 -7.104 5.404 1.00 21.53ATOM 1673 O PHE 876 29.788 -7.616 4.917 1.00 21.91ATOM 1674 N THR 877 28.806 -5.952 6.063 1.00 21.43ATOM 1675 CA THR 877 30.063 -5.220 6.249 1.00 22.00ATOM 1676 CB THR 877 29.824 -3.884 7.014 1.00 20.78ATOM 1677 CG2 THR 877 31.108 -3.079 7.227 1.00 15.00ATOM 1678 OG1 THR 877 28.924 -3.062 6.286 1.00 15.00ATOM 1679 C THR 877 31.088 -6.071 6.987 1.00 21.87ATOM 1680 O THR 877 32.265 -6.025 6.661 1.00 21.92ATOM 1681 N PHE 878 30.648 -6.834 7.984 1.00 22.33ATOM 1682 CA PHE 878 31.568 -7.694 8.727 1.00 23.05ATOM 1683 CB PHE 878 30.867 -8.381 9.899 1.00 22.33ATOM 1684 CG PHE 878 31.666 -9.513 10.495 1.00 21.73ATOM 1685 CD1 PHE 878 32.782 -9.254 11.288 1.00 21.25ATOM 1686 CD2 PHE 878 31.317 -10.838 10.241 1.00 21.33ATOM 1687 CE1 PHE 878 33.538 -10.301 11.822 1.00 20.86ATOM 1688 CE2 PHE 878 32.069 -11.889 10.771 1.00 21.01ATOM 1689 CZ PHE 878 33.181 -11.618 11.562 1.00 21.09ATOM 1690 C PHE 878 32.092 -8.766 7.775 1.00 23.92ATOM 1691 O PHE 878 33.307 -8.936 7.618 1.00 23.91ATOM 1692 N ASP 879 31.166 -9.503 7.160 1.00 24.70ATOM 1693 CA ASP 879 31.545 -10.540 6.203 1.00 25.62ATOM 1694 CB ASP 879 30.318 -11.110 5.483 1.00 26.61ATOM 1695 CG ASP 879 29.466 -12.011 6.373 1.00 28.26ATOM 1696 OD1 ASP 879 29.869 -12.286 7.532 1.00 29.19ATOM 1697 OD2 ASP 879 28.388 -12.446 5.903 1.00 28.52ATOM 1698 C ASP 879 32.485 -9.937 5.161 1.00 25.71ATOM 1699 O ASP 879 33.446 -10.586 4.743 1.00 25.95ATOM 1700 N LEU 880 32.224 -8.690 4.759 1.00 25.33ATOM 1701 CA LEU 880 33.050 -8.038 3.740 1.00 25.14ATOM 1702 CB LEU 880 32.420 -6.706 3.288 1.00 24.49ATOM 1703 CG LEU 880 33.171 -5.970 2.157 1.00 24.36ATOM 1704 CD1 LEU 880 33.263 -6.890 0.941 1.00 24.34ATOM 1705 CD2 LEU 880 32.486 -4.669 1.777 1.00 23.43ATOM 1706 C LEU 880 34.494 -7.800 4.174 1.00 24.87ATOM 1707 O LEU 880 35.414 -7.954 3.384 1.00 24.35ATOM 1708 N LEU 881 34.672 -7.424 5.433 1.00 25.68ATOM 1709 CA LEU 881 35.984 -7.151 6.010 1.00 26.42ATOM 1710 CB LEU 881 35.823 -6.684 7.459 1.00 26.13ATOM 1711 CG LEU 881 37.124 -6.552 8.247 1.00 25.98ATOM 1712 CD1 LEU 881 37.921 -5.392 7.676 1.00 25.56ATOM 1713 CD2 LEU 881 36.828 -6.335 9.726 1.00 26.07ATOM 1714 C LEU 881 36.905 -8.358 5.988 1.00 27.40ATOM 1715 O LEU 881 38.030 -8.284 5.498 1.00 27.41ATOM 1716 N ILE 882 36.416 -9.466 6.532 1.00 28.64ATOM 1717 CA ILE 882 37.187 -10.694 6.610 1.00 30.19ATOM 1718 CB ILE 882 36.353 -11.858 7.171 1.00 29.99ATOM 1719 CG2 ILE 882 37.279 -13.022 7.499 1.00 30.50ATOM 1720 CG1 ILE 882 35.594 -11.420 8.431 1.00 29.82ATOM 1721 CD1 ILE 882 36.488 -10.926 9.537 1.00 28.87ATOM 1722 C ILE 882 37.734 -11.143 5.270 1.00 31.79ATOM 1723 O ILE 882 38.813 -11.731 5.212 1.00 32.60ATOM 1724 N LYS 883 36.997 -10.886 4.192 1.00 33.37ATOM 1725 CA LYS 883 37.456 -11.298 2.873 1.00 35.08ATOM 1726 CB LYS 883 36.473 -12.298 2.254 1.00 35.22ATOM 1727 CG LYS 883 35.030 -12.122 2.676 1.00 35.39ATOM 1728 CD LYS 883 34.263 -13.428 2.488 1.00 35.67ATOM 1729 CE LYS 883 33.018 -13.508 3.387 1.00 35.63ATOM 1730 NZ LYS 883 33.347 -13.507 4.849 1.00 34.49ATOM 1731 C LYS 883 37.729 -10.165 1.901 1.00 36.23ATOM 1732 O LYS 883 37.951 -10.409 0.720 1.00 36.16ATOM 1733 N SER 884 37.735 -8.929 2.394 1.00 38.01ATOM 1734 CA SER 884 38.010 -7.781 1.535 1.00 39.99ATOM 1735 CB SER 884 37.908 -6.480 2.331 1.00 39.82ATOM 1736 OG SER 884 38.779 -6.500 3.445 1.00 40.42ATOM 1737 C SER 884 39.421 -7.946 0.991 1.00 41.45ATOM 1738 O SER 884 39.857 -7.222 0.100 1.00 41.65ATOM 1739 N HIS 885 40.129 -8.916 1.552 1.00 43.33ATOM 1740 CA HIS 885 41.485 -9.216 1.146 1.00 45.27ATOM 1741 CB HIS 885 42.079 -10.274 2.085 1.00 46.21ATOM 1742 CG HIS 885 41.975 -9.918 3.539 1.00 47.51ATOM 1743 CD2 HIS 885 42.927 -9.619 4.457 1.00 47.92ATOM 1744 ND1 HIS 885 40.765 -9.800 4.193 1.00 47.61ATOM 1745 CE1 HIS 885 40.977 -9.443 5.448 1.00 47.80ATOM 1746 NE2 HIS 885 42.280 -9.326 5.635 1.00 48.03ATOM 1747 C HIS 885 41.482 -9.732 -0.291 1.00 46.02ATOM 1748 O HIS 885 42.195 -9.210 -1.145 1.00 46.12ATOM 1749 N MET 886 40.650 -10.739 -0.545 1.00 46.78ATOM 1750 CA MET 886 40.542 -11.377 -1.856 1.00 47.47ATOM 1751 CB MET 886 40.210 -12.861 -1.660 1.00 48.40ATOM 1752 CG MET 886 40.207 -13.696 -2.934 1.00 49.75ATOM 1753 SD MET 886 39.580 -15.376 -2.674 1.00 51.35ATOM 1754 CE MET 886 37.809 -15.116 -2.950 1.00 50.99ATOM 1755 C MET 886 39.533 -10.762 -2.842 1.00 47.47ATOM 1756 O MET 886 39.399 -11.242 -3.966 1.00 47.36ATOM 1757 N VAL 887 38.821 -9.713 -2.441 1.00 47.33ATOM 1758 CA VAL 887 37.851 -9.109 -3.351 1.00 46.96ATOM 1759 CB VAL 887 36.451 -9.054 -2.723 1.00 47.00ATOM 1760 CG1 VAL 887 35.425 -8.807 -3.799 1.00 47.21ATOM 1761 CG2 VAL 887 36.149 -10.356 -2.003 1.00 47.16ATOM 1762 C VAL 887 38.271 -7.702 -3.772 1.00 46.99ATOM 1763 0 VAL 887 37.553 -7.017 -4.511 1.00 46.75ATOM 1764 N SER 888 39.435 -7.279 -3.283 1.00 46.66ATOM 1765 CA SER 888 40.008 -5.982 -3.617 1.00 46.35ATOM 1766 CB SER 888 40.275 -5.926 -5.123 1.00 46.40ATOM 1767 OG SER 888 41.043 -7.042 -5.542 1.00 45.75ATOM 1768 C SER 888 39.180 -4.765 -3.200 1.00 46.54ATOM 1769 O SER 888 38.840 -3.922 -4.038 1.00 46.44ATOM 1770 N VAL 889 38.876 -4.666 -1.907 1.00 46.50ATOM 1771 CA VAL 889 38.104 -3.546 -1.375 1.00 46.35ATOM 1772 CB VAL 889 36.750 -4.024 -0.836 1.00 46.08ATOM 1773 CG1 VAL 889 35.952 -2.849 -0.321 1.00 46.13ATOM 1774 CG2 VAL 889 35.986 -4.742 -1.925 1.00 46.06ATOM 1775 C VAL 889 38.864 -2.854 -0.243 1.00 46.74ATOM 1776 O VAL 889 39.218 -3.490 0.751 1.00 46.95ATOM 1777 N ASP 890 39.117 -1.554 -0.391 1.00 46.98ATOM 1778 CA ASP 890 39.834 -0.804 0.640 1.00 47.18ATOM 1779 CB ASP 890 40.261 0.589 0.145 1.00 48.23ATOM 1780 CG ASP 890 40.782 0.586 -1.275 1.00 49.20ATOM 1781 OD1 ASP 890 41.642 -0.261 -1.600 1.00 50.24ATOM 1782 OD2 ASP 890 40.339 1.452 -2.065 1.00 49.63ATOM 1783 C ASP 890 38.946 -0.595 1.863 1.00 46.72ATOM 1784 O ASP 890 37.725 -0.488 1.748 1.00 46.63ATOM 1785 N PHE 891 39.568 -0.534 3.033 1.00 46.21ATOM 1786 CA PHE 891 38.850 -0.284 4.274 1.00 45.79ATOM 1787 CB PHE 891 38.739 -1.551 5.129 1.00 44.93ATOM 1788 CG PHE 891 37.417 -2.260 5.003 1.00 43.95ATOM 1789 CD1 PHE 891 37.284 -3.385 4.192 1.00 43.65ATOM 1790 CD2 PHE 891 36.300 -1.795 5.683 1.00 43.28ATOM 1791 CE1 PHE 891 36.060 -4.032 4.064 1.00 43.03ATOM 1792 CE2 PHE 891 35.071 -2.437 5.561 1.00 42.87ATOM 1793 CZ PHE 891 34.952 -3.557 4.750 1.00 42.99ATOM 1794 C PHE 891 39.647 0.764 5.028 1.00 46.31ATOM 1795 O PHE 891 40.804 0.535 5.376 1.00 46.19ATOM 1796 N PRO 892 39.056 1.945 5.258 1.00 46.87ATOM 1797 CD PRO 892 37.779 2.479 4.761 1.00 47.03ATOM 1798 CA PRO 892 39.800 2.973 5.989 1.00 47.86ATOM 1799 CB PRO 892 38.777 4.100 6.126 1.00 47.55ATOM 1800 CG PRO 892 38.002 3.981 4.856 1.00 47.27ATOM 1801 C PRO 892 40.272 2.421 7.337 1.00 48.77ATOM 1802 O PRO 892 39.559 1.660 7.994 1.00 48.53ATOM 1803 N GLU 893 41.478 2.804 7.737 1.00 49.95ATOM 1804 CA GLU 893 42.069 2.330 8.987 1.00 50.96ATOM 1805 CB GLU 893 43.278 3.194 9.349 1.00 51.80ATOM 1806 CG GLU 893 44.243 2.521 10.314 1.00 53.18ATOM 1807 CD GLU 893 44.688 1.145 9.833 1.00 53.98ATOM 1808 OE1 GLU 893 43.850 0.215 9.823 1.00 54.56ATOM 1809 OE2 GLU 893 45.874 0.995 9.461 1.00 54.43ATOM 1810 C GLU 893 41.108 2.267 10.177 1.00 50.91ATOM 1811 O GLU 893 41.006 1.232 10.834 1.00 51.08ATOM 1812 N MET 894 40.415 3.368 10.454 1.00 50.86ATOM 1813 CA MET 894 39.468 3.418 11.567 1.00 50.94ATOM 1814 CB MET 894 38.942 4.846 11.768 1.00 51.97ATOM 1815 CG MET 894 39.769 5.723 12.688 1.00 53.43ATOM 1816 SD MET 894 39.094 7.410 12.777 1.00 55.12ATOM 1817 CE MET 894 40.330 8.326 11.783 1.00 54.74ATOM 1818 C MET 894 38.278 2.495 11.337 1.00 50.28ATOM 1819 O MET 894 37.617 2.069 12.287 1.00 50.13ATOM 1820 N MET 895 38.007 2.204 10.068 1.00 49.44ATOM 1821 CA MET 895 36.885 1.351 9.682 1.00 48.35ATOM 1822 CB MET 895 36.715 1.388 8.155 1.00 49.15ATOM 1823 CG MET 895 35.410 0.824 7.630 1.00 49.68ATOM 1824 SD MET 895 34.001 1.826 8.121 1.00 51.13ATOM 1825 CE MET 895 34.136 3.188 6.979 1.00 50.63ATOM 1826 C MET 895 37.094 -0.089 10.152 1.00 46.87ATOM 1827 O MET 895 36.336 -0.597 10.975 1.00 46.59ATOM 1828 N ALA 896 38.136 -0.729 9.634 1.00 45.22ATOM 1829 CA ALA 896 38.442 -2.113 9.977 1.00 43.83ATOM 1830 CB ALA 896 39.706 -2.563 9.247 1.00 43.37ATOM 1831 C ALA 896 38.601 -2.324 11.481 1.00 42.67ATOM 1832 O ALA 896 38.473 -3.440 11.976 1.00 42.42ATOM 1833 N GLU 897 38.872 -1.243 12.200 1.00 41.32ATOM 1834 CA GLU 897 39.058 -1.306 13.640 1.00 39.88ATOM 1835 CB GLU 897 39.828 -0.058 14.101 1.00 40.74ATOM 1836 CG GLU 897 40.690 -0.236 15.353 1.00 41.25ATOM 1837 CD GLU 897 41.768 0.849 15.491 1.00 41.90ATOM 1838 OE1 GLU 897 42.665 0.918 14.619 1.00 41.86ATOM 1839 OE2 GLU 897 41.723 1.632 16.468 1.00 42.21ATOM 1840 C GLU 897 37.685 -1.390 14.313 1.00 38.68ATOM 1841 O GLU 897 37.346 -2.397 14.944 1.00 38.45ATOM 1842 N ILE 898 36.889 -0.339 14.159 1.00 36.89ATOM 1843 CA ILE 898 35.558 -0.308 14.745 1.00 35.29ATOM 1844 CB ILE 898 34.799 0.981 14.366 1.00 35.18ATOM 1845 CG2 ILE 898 33.459 1.003 15.063 1.00 34.79ATOM 1846 CG1 ILE 898 35.61 2.212 14.782 1.00 35.43ATOM 1847 CD1 ILE 898 34.99 3.555 14.378 1.00 34.84ATOM 1848 C ILE 898 34.728 -1.513 14.307 1.00 33.92ATOM 1849 O ILE 898 33.926 -2.034 15.087 1.00 33.92ATOM 1850 N ILE 899 34.912 -1.951 13.064 1.00 32.03ATOM 1851 CA ILE 899 34.173 -3.108 12.566 1.00 30.47ATOM 1852 CB ILE 899 34.485 -3.404 11.099 1.00 30.35ATOM 1853 CG2 ILE 899 33.746 -4.653 10.663 1.00 29.70ATOM 1854 CG1 ILE 899 34.090 -2.222 10.221 1.00 30.03ATOM 1855 CD1 ILE 899 34.481 -2.407 8.775 1.00 29.09ATOM 1856 C ILE 899 34.528 -4.370 13.343 1.00 29.56ATOM 1857 O ILE 899 33.668 -5.007 13.934 1.00 29.56ATOM 1858 N SER 900 35.809 -4.717 13.339 1.00 28.34ATOM 1859 CA SER 900 36.283 -5.916 14.007 1.00 27.55ATOM 1860 CB SER 900 37.767 -6.124 13.711 1.00 27.86ATOM 1861 OG SER 900 38.539 -5.030 14.182 1.00 29.18ATOM 1862 C SER 900 36.072 -5.940 15.511 1.00 26.83ATOM 1863 O SER 900 35.911 -7.016 16.108 1.00 26.70ATOM 1864 N VAL 901 36.066 -4.761 16.122 1.00 25.47ATOM 1865 CA VAL 901 35.914 -4.669 17.565 1.00 24.36ATOM 1866 CB VAL 901 36.810 -3.539 18.132 1.00 24.53ATOM 1867 CG1 VAL 901 36.613 -3.401 19.635 1.00 24.63ATOM 1868 CG2 VAL 901 38.261 -3.838 17.826 1.00 24.17ATOM 1869 C VAL 901 34.489 -4.457 18.052 1.00 23.82ATOM 1870 O VAL 901 34.056 -5.107 18.998 1.00 23.59ATOM 1871 N GLN 902 33.754 -3.565 17.404 1.00 23.25ATOM 1872 CA GLN 902 32.396 -3.264 17.836 1.00 23.10ATOM 1873 CB GLN 902 32.128 -1.771 17.652 1.00 23.43ATOM 1874 CG GLN 902 33.026 -0.856 18.468 1.00 24.40ATOM 1875 CD GLN 902 32.724 -0.898 19.960 1.00 25.11ATOM 1876 OE1 GLN 902 32.836 0.108 20.652 1.00 25.82ATOM 1877 NE2 GLN 902 32.353 -2.070 20.463 1.00 26.55ATOM 1878 C GLN 902 31.285 -4.062 17.150 1.00 22.80ATOM 1879 O GLN 902 30.330 -4.488 17.802 1.00 22.81ATOM 1880 N VAL 903 31.409 -4.260 15.840 1.00 21.89ATOM 1881 CA VAL 903 30.397 -4.985 15.083 1.00 21.01ATOM 1882 CB VAL 903 30.753 -4.987 13.568 1.00 20.43ATOM 1883 CG1 VAL 903 29.811 -5.891 12.783 1.00 20.60ATOM 1884 CG2 VAL 903 30.625 -3.572 13.033 1.00 19.46ATOM 1885 C VAL 903 30.118 -6.404 15.594 1.00 20.85ATOM 1886 O VAL 903 28.962 -6.798 15.710 1.00 19.49ATOM 1887 N PRO 904 31.172 -7.182 15.925 1.00 21.30ATOM 1888 CD PRO 904 32.614 -6.943 15.734 1.00 20.97ATOM 1889 CA PRO 904 30.941 -8.545 16.421 1.00 21.34ATOM 1890 CB PRO 904 32.356 -9.114 16.548 1.00 20.99ATOM 1891 CG PRO 904 33.120 -8.353 15.512 1.00 21.65ATOM 1892 C PRO 904 30.175 -8.585 17.750 1.00 22.05ATOM 1893 O PRO 904 29.548 -9.600 18.077 1.00 22.76ATOM 1894 N LYS 905 30.234 -7.503 18.524 1.00 21.69ATOM 1895 CA LYS 905 29.512 -7.464 19.791 1.00 22.05ATOM 1896 CB LYS 905 29.823 -6.183 20.577 1.00 22.91ATOM 1897 CG LYS 905 31.236 -6.070 21.145 1.00 23.84ATOM 1898 CD LYS 905 31.333 -4.835 22.041 1.00 24.82ATOM 1899 CE LYS 905 32.692 -4.710 22.736 1.00 25.65ATOM 1900 NZ LYS 905 32.716 -3.560 23.693 1.00 25.72ATOM 1901 C LYS 905 28.023 -7.491 19.477 1.00 21.85ATOM 1902 O LYS 905 27.208 -7.982 20.255 1.00 21.42ATOM 1903 N ILE 906 27.675 -6.929 18.330 1.00 21.67ATOM 1904 CA ILE 906 26.286 -6.873 17.903 1.00 21.52ATOM 1905 CB ILE 906 26.078 -5.742 16.827 1.00 21.27ATOM 1906 CG2 ILE 906 24.655 -5.766 16.313 1.00 20.46ATOM 1907 CG1 ILE 906 26.442 -4.380 17.434 1.00 20.69ATOM 1908 CD1 ILE 906 26.272 -3.193 16.517 1.00 21.16ATOM 1909 C ILE 906 25.865 -8.226 17.331 1.00 21.33ATOM 1910 O ILE 906 24.902 -8.827 17.800 1.00 21.55ATOM 1911 N LEU 907 26.607 -8.715 16.342 1.00 20.88ATOM 1912 CA LEU 907 26.274 -9.990 15.717 1.00 21.31ATOM 1913 CB LEU 907 27.244 -10.280 14.561 1.00 19.40ATOM 1914 CG LEU 907 27.380 -9.060 13.634 1.00 18.63ATOM 1915 CD1 LEU 907 28.333 -9.370 12.509 1.00 17.46ATOM 1916 CD2 LEU 907 26.008 -8.646 13.092 1.00 17.25ATOM 1917 C LEU 907 26.225 -11.165 16.695 1.00 21.62ATOM 1918 O LEU 907 25.360 -12.037 16.563 1.00 22.68ATOM 1919 N SER 908 27.118 -11.177 17.685 1.00 21.63ATOM 1920 CA SER 908 27.150 -12.266 18.664 1.00 22.10ATOM 1921 CB SER 908 28.564 -12.433 19.238 1.00 21.84ATOM 1922 OG SER 908 28.952 -11.279 19.949 1.00 22.32ATOM 1923 C SER 908 26.146 -12.060 19.802 1.00 22.09ATOM 1924 O SER 908 26.086 -12.862 20.740 1.00 22.15ATOM 1925 N GLY 909 25.376 -10.976 19.730 1.00 22.11ATOM 1926 CA GLY 909 24.361 -10.718 20.743 1.00 22.44ATOM 1927 C GLY 909 24.707 -9.946 22.006 1.00 22.41ATOM 1928 O GLY 909 23.843 -9.735 22.854 1.00 22.66ATOM 1929 N LYS 910 25.950 -9.519 22.152 1.00 22.78ATOM 1930 CA LYS 910 26.332 -8.773 23.344 1.00 23.71ATOM 1931 CB LYS 910 27.838 -8.650 23.410 1.00 24.13ATOM 1932 CG LYS 910 28.521 -9.978 23.588 1.00 25.11ATOM 1933 CD LYS 910 30.006 -9.783 23.775 1.00 25.46ATOM 1934 CE LYS 910 30.613 -11.053 24.288 1.00 26.49ATOM 1935 N2 LYS 910 29.764 -11.585 25.391 1.00 27.68ATOM 1936 C LYS 910 25.702 -7.381 23.438 1.00 24.13ATOM 1937 O LYS 910 25.442 -6.880 24.540 1.00 23.96ATOM 1938 N VAL 911 25.465 -6.769 22.278 1.00 24.03ATOM 1939 CA VAL 911 24.869 -5.445 22.182 1.00 24.31ATOM 1940 CB VAL 911 25.868 -4.413 21.588 1.00 24.16ATOM 1941 CG1 VAL 911 26.588 -5.010 20.444 1.00 25.18ATOM 1942 CG2 VAL 911 25.142 -3.180 21.086 1.00 24.84ATOM 1943 C VAL 911 23.672 -5.582 21.272 1.00 24.68ATOM 1944 O VAL 911 23.781 -6.139 20.185 1.00 25.01ATOM 1945 N LYS 912 22.527 -5.081 21.710 1.00 24.92ATOM 1946 CA LYS 912 21.322 -5.192 20.910 1.00 25.57ATOM 1947 CB LYS 912 20.429 -6.297 21.470 1.00 26.08ATOM 1948 CG LYS 912 21.049 -7.676 21.478 1.00 26.96ATOM 1949 CD LYS 912 20.221 -8.591 22.357 1.00 28.27ATOM 1950 CE LYS 912 20.096 -7.986 23.747 1.00 28.84ATOM 1951 NZ LYS 912 21.426 -7.849 24.424 1.00 28.86ATOM 1952 C LYS 912 20.516 -3.903 20.836 1.00 25.87ATOM 1953 O LYS 912 20.561 -3.069 21.742 1.00 25.78ATOM 1954 N PRO 913 19.763 -3.731 19.742 1.00 26.36ATOM 1955 CD PRO 913 19.645 -4.672 18.615 1.00 26.55ATOM 1956 CA PRO 913 18.927 -2.550 19.520 1.00 26.76ATOM 1957 CB PRO 913 18.356 -2.777 18.118 1.00 26.68ATOM 1958 CG PRO 913 19.296 -3.755 17.493 1.00 27.35ATOM 1959 C PRO 913 17.808 -2.527 20.549 1.00 27.50ATOM 1960 O PRO 913 17.435 -3.571 21.088 1.00 27.19ATOM 1961 N ILE 914 17.288 -1.335 20.826 1.00 28.15ATOM 1962 CA ILE 914 16.168 -1.190 21.743 1.00 28.95ATOM 1963 CB ILE 914 16.344 0.020 22.690 1.00 29.11ATOM 1964 CG2 ILE 914 15.077 0.212 23.525 1.00 28.84ATOM 1965 CG1 ILE 914 17.563 -0.195 23.598 1.00 29.16ATOM 1966 CD1 ILE 914 17.882 0.986 24.507 1.00 29.16ATOM 1967 C ILE 914 14.955 -0.942 20.848 1.00 29.58ATOM 1968 O ILE 914 14.896 0.069 20.148 1.00 30.48ATOM 1969 N TYR 915 14.010 -1.879 20.844 1.00 29.76ATOM 1970 CA TYR 915 12.791 -1.759 20.042 1.00 29.79ATOM 1971 CB TYR 915 12.344 -3.133 19.514 1.00 29.35ATOM 1972 CG TYR 915 13.194 -3.687 18.405 1.00 29.23ATOM 1973 CD1 TYR 915 14.242 -4.574 18.667 1.00 29.36ATOM 1974 CE1 TYR 915 15.055 -5.047 17.641 1.00 29.21ATOM 1975 CD2 TYR 915 12.981 -3.289 17.092 1.00 29.29ATOM 1976 CE2 TYR 915 13.785 -3.749 16.064 1.00 29.70ATOM 1977 CZ TYR 915 14.818 -4.626 16.340 1.00 29.95ATOM 1978 OH TYR 915 15.597 -5.080 15.296 1.00 31.15ATOM 1979 C TYR 915 11.641 -1.180 20.861 1.00 29.93ATOM 1980 O TYR 915 11.549 -1.412 22.060 1.00 30.36ATOM 1981 N PHE 916 10.765 -0.426 20.217 1.00 29.99ATOM 1982 CA PHE 916 9.610 0.105 20.917 1.00 30.60ATOM 1983 CB PHE 916 9.025 1.319 20.191 1.00 30.23ATOM 1984 CG PHE 916 9.744 2.602 20.478 1.00 30.62ATOM 1985 CD1 PHE 916 9.659 3.192 21.731 1.00 30.55ATOM 1986 CD2 PHE 916 10.503 3.226 19.494 1.00 30.58ATOM 1987 CE1 PHE 916 10.315 4.381 22.000 1.00 30.34ATOM 1988 CE2 PHE 916 11.163 4.417 19.757 1.00 30.86ATOM 1989 CZ PHE 916 11.068 4.994 21.010 1.00 30.74ATOM 1990 C PHE 916 8.564 -1.014 20.982 1.00 31.09ATOM 1991 O PHE 916 7.976 -1.259 22.038 1.00 31.66ATOM 1992 N HIS 917 8.345 -1.696 19.858 1.00 31.14ATOM 1993 CA HIS 917 7.373 -2.782 19.802 1.00 31.46ATOM 1994 CB HIS 917 6.375 -2.579 18.651 1.00 30.70ATOM 1995 CG HIS 917 5.843 -1.185 18.534 1.00 29.89ATOM 1996 CD2 HIS 917 4.695 -0.628 18.984 1.00 29.89ATOM 1997 ND1 HIS 917 6.514 -0.188 17.863 1.00 29.93ATOM 1998 CE1 HIS 917 5.800 0.924 17.899 1.00 29.50ATOM 1999 NE2 HIS 917 4.691 0.683 18.574 1.00 29.71ATOM 2000 C HIS 917 8.093 -4.099 19.590 1.00 32.03ATOM 2001 O HIS 917 9.218 -4.116 19.102 1.00 33.01ATOM 2002 N ALA 918 7.442 -5.201 19.949 1.00 32.62ATOM 2003 CA ALA 918 8.025 -6.529 19.777 1.00 32.98ATOM 2004 CB ALA 918 7.769 -7.382 21.013 1.00 33.52ATOM 2005 C ALA 918 7.421 -7.201 18.551 1.00 33.16ATOM 2006 O ALA 918 7.922 -7.049 17.432 1.00 33.55
Claims (24)
1.一种抑制其需要患者的激素依赖性肿瘤细胞生长的方法,该方法包括给予所述患者有效量的选择性雄激素受体调节剂,其中所述选择性雄激素受体调节剂对所述激素依赖性肿瘤呈现拮抗作用,而对含雄激素受体的其它非肿瘤组织无活性或呈现激动活性。
2.权利要求1的方法,其中所述肿瘤细胞是前列腺肿瘤细胞,并且其中除对所述肿瘤细胞呈现拮抗作用而对含雄激素受体的其它非肿瘤组织无活性或呈现激动活性外,所述选择性雄激素受体调节剂还对正常的前列腺组织呈现激动作用、拮抗作用或无活性。
3.权利要求1的方法,其中所述选择性雄激素受体调节剂对含雄激素受体的其它非肿瘤组织呈现激动活性。
4.权利要求1的方法,其中所述选择性雄激素受体调节剂对含雄激素受体的其它非肿瘤组织无活性。
5.权利要求1的方法,其中所述激素依赖性肿瘤是前列腺癌。
6.权利要求1的方法,其中所述含雄激素受体的其它非肿瘤组织包括一种或多种下列组织:精囊、雄性和雌性生殖器、皮肤、睾丸、卵巢、软骨、皮脂腺、毛囊、汗腺、肌肉、胃肠道囊状细胞、甲状腺滤泡细胞、肾上腺皮质、肝脏、松果体、骨、基质细胞、肾小管、膀胱和/或脑皮质及皮质下区。
7.权利要求6的方法,其中所述含雄激素受体的其它非肿瘤组织包括一种或多种下列组织:心肌、骨骼肌和/或平滑肌。
8.一种选择性雄激素受体调节剂,该调节剂对激素依赖性肿瘤呈现拮抗活性,而对含雄激素受体的其它非肿瘤组织无活性或呈现激动活性。
9.一种治疗可通过给予权利要求8的选择性雄激素受体调节剂治疗的病症的方法,该方法包括给予患者有效量的所述选择性雄激素受体调节剂,其中所述病症选自:女性多毛症、痤疮、皮脂溢、阿尔茨海默氏病、雄激素性脱发、性腺机能减退、多毛症、良性前列腺肥大、前列腺肿瘤、含雄激素受体的良性或恶性肿瘤细胞的治疗、胰腺癌、调节VEGF表达而用作抗血管发生剂、骨质疏松症、抑制精子生成、性欲、恶质病、子宫内膜异位症、多囊卵巢综合症、厌食症、雄激素依赖性的年龄相关性疾病和病症、雄性绝经、雄性激素替代、雄性及雌性性功能障碍以及抑制非卧床患者的肌肉萎缩。
10.一种鉴定权利要求8的选择性雄激素受体调节剂的方法,该方法包括筛选试验化合物对激素依赖性肿瘤细胞系生长的抑制作用,以及筛选所述试验化合物对含有雄激素受体的非恶性细胞系的雄激素受体活性,其中抑制激素依赖性肿瘤细胞系的生长,同时对非恶性细胞系无雄激素受体活性或者呈现激活雄激素受体活性的所述试验化合物鉴定为所述选择性雄激素受体调节剂。
11.一种鉴定权利要求8的选择性雄激素受体调节剂的方法,该方法包括筛选既抑制激素依赖性肿瘤生长,又对带有所述激素依赖性肿瘤的动物模型体内含有雄激素受体的其它非恶性组织的雄激素受体具有活化作用的试验化合物,其中抑制激素依赖性肿瘤的生长,同时对所述动物模型的非恶性组织无雄激素受体活性或者呈现雄激素受体活性活化作用的试验化合物鉴定为所述选择性雄激素受体调节剂。
12.一种由表A的结构配位定义的三维晶体结构的分子或分子复合物。
13.一种分子或分子复合物,其包含表A的AR-LBD氨基酸V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907结构配位定义的整个或任何部分的配体结合位点;或者所述分子或分子复合物的突变体或同系物。
14.权利要求13的分子或分子复合物,其中所述突变体或同系物包含结合空穴,该空穴与所述AR-LBD氨基酸主链原子的均方根偏差不超过1.5埃或者与所述AR-LBD氨基酸具有30%的序列同一性。
15.一种分子或分子复合物,其包含表A的AR-LBD氨基酸N705、W741、Q711、R752、F764、T877、M895和I898的结构配位定义的整个或任何部分的配体结合位点;或者所述分子或分子复合物的突变体或同系物。
16.权利要求15的分子或分子复合物,其中所述突变体或同系物包含结合空穴,该空穴与所述AR-LBD氨基酸主链原子的均方根偏差不超过1.5埃或者与所述AR-LBD氨基酸具有30%的序列同一性。
17.一种机器可读数据储存介质,其包括机器可读数据编码的数据贮存材料,其中所述数据由表A的AR-LBD/AR-LBD配体或配体复合物或者所述复合物同系物的结构配位定义,其中所述同系物包含与所述复合物主链原子的均方根偏差不超过3.0埃的主链原子。
18.权利要求17的机器可读数据储存介质,其中所述AR-LBD/AR-LBD配体或配体复合物是与所述氨基酸主链原子的均方根偏差不超过2.0埃的同系物。
19.一种机器可读数据储存介质,其包括第一套机器可读数据编码的数据贮存材料,所述数据包含傅立叶转换的表A的AR-LBD/AR-LBD配体的至少一部分结构配位;当其结合包含未知结构的分子或分子复合物的X-射线衍射图谱的第二套机器可读数据时,可用所述第一套和第二套数据按照说明书编程的机器,确定对应于所述第二套机器可读数据的至少一部分结构配位;所述第一套数据和所述第二套数据。
20.一种AR调节剂的AR-LBD结合位点,其中所述配体的一部分与表A的AR-LBD的任何部分或所有的残基V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907以范德华力接触或氢键键合接触。
21.根据权利要求20的结合位点,其中所述AR-LBD是与表A的AR-LBD的残基V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q71 1、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907具有25%-95%同一性的同系物或突变体。
22.一种设计雄激素受体合成配体的计算机方法,其包括:
a.利用包含AR-LBD/AR-LBD配体复合物的晶体蛋白质的三维模型,确定至少一个AR-LBD互作氨基酸,后者与至少一个所述AR-LBD配体的第一化学部分相互作用;和
b.选择至少一个所述第一化学部分的化学修饰,产生第二化学部分,同所述互作氨基酸与所述第一化学部分之间的相互作用相比,第二化学部分具有或者降低或者增加所述互作氨基酸与该第二化学部分之间的相互作用的结构。
23.一种鉴定调节雄激素受体活性的化合物的方法,该方法包括任意组合的下列步骤:
a.建立空间上适合于表A结构配位定义的AR-LBD的试验化合物模型,或者利用AR-LBD、突变AR-LBD或AR-LBD同系物或其部分的三维结构模型;
b.利用权利要求20给出的所述结构配位或配体结合位点,鉴定结构和化学特征;
c.利用所鉴定的结构或化学特征,设计或选择作为潜在SARM的化合物;
d.利用所述三维结构模型或配体结合位点,设计或选择作为潜在SARM化合物;
e.合成潜在SARM;
f.用特征为试验化合物结合所述AR-LBD的测定,筛选潜在SARM;
g.修饰或置换AR-LBD中的一个或多个氨基酸,所述AR-LBD选自表A以下AR-LBD:V685、L700、L701、S702、S703、L704、N705、E706、L707、G708、E709、Q711、A735、I737、Q738、Y739、S740、W741、M742、G743、L744、M745、V746、F747、A748、M749、G750、R752、Y763、F764、A765、L768、F770、M780、M787、I869、L873、H874、F876、T877、F878、L880、L881、V889、F891、P892、E893、M894、M895、A896、E897、I898、I899、S900、V901、Q902、V903、P904、K905、I906、L907。
24.一种药用组合物,其包含选择性雄激素受体调节剂和药学上可接受的载体,其中根据权利要求10、11、22或23的方法选择或设计所述选择性雄激素受体调节剂。
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- 2001-06-20 JP JP2002505365A patent/JP2004509072A/ja active Pending
- 2001-06-20 EP EP01967933A patent/EP1299094A2/en not_active Withdrawn
- 2001-06-20 IL IL15271901A patent/IL152719A0/xx unknown
- 2001-06-20 KR KR1020027017856A patent/KR20030016310A/ko not_active Application Discontinuation
- 2001-06-20 US US09/885,827 patent/US6960474B2/en not_active Expired - Lifetime
- 2001-06-20 CZ CZ20024214A patent/CZ20024214A3/cs unknown
- 2001-06-20 CA CA002413417A patent/CA2413417A1/en not_active Abandoned
- 2001-06-20 CN CN01812037A patent/CN1454083A/zh active Pending
- 2001-06-20 WO PCT/US2001/019665 patent/WO2002000617A2/en not_active Application Discontinuation
- 2001-06-20 MX MXPA02012605A patent/MXPA02012605A/es unknown
- 2001-06-20 AU AU8821301A patent/AU8821301A/xx active Pending
- 2001-06-20 AU AU2001288213A patent/AU2001288213B2/en not_active Ceased
- 2001-06-20 HU HU0303172A patent/HUP0303172A3/hu unknown
- 2001-06-20 BR BR0111298-8A patent/BR0111298A/pt not_active IP Right Cessation
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2002
- 2002-12-23 NO NO20026194A patent/NO20026194L/no not_active Application Discontinuation
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2005
- 2005-05-17 US US11/130,935 patent/US20050256048A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102875556A (zh) * | 2011-07-12 | 2013-01-16 | 上海药明康德新药开发有限公司 | (4s)-1-取代-2,5-二氮杂双环[2,2,1]庚烷衍生物及制备方法 |
CN105640645A (zh) * | 2014-11-26 | 2016-06-08 | 华东医院 | 一种多囊卵巢动物模型的建立方法及其应用 |
Also Published As
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EP1299094A2 (en) | 2003-04-09 |
CZ20024214A3 (cs) | 2003-04-16 |
WO2002000617A3 (en) | 2003-01-30 |
IL152719A0 (en) | 2003-06-24 |
NO20026194L (no) | 2003-02-26 |
WO2002000617A2 (en) | 2002-01-03 |
US6960474B2 (en) | 2005-11-01 |
MXPA02012605A (es) | 2003-05-14 |
AU8821301A (en) | 2002-01-08 |
BR0111298A (pt) | 2005-05-10 |
HUP0303172A3 (en) | 2006-05-29 |
HUP0303172A2 (hu) | 2003-12-29 |
AU2001288213B2 (en) | 2005-04-14 |
US20020173445A1 (en) | 2002-11-21 |
NO20026194D0 (no) | 2002-12-23 |
KR20030016310A (ko) | 2003-02-26 |
US20050256048A1 (en) | 2005-11-17 |
JP2004509072A (ja) | 2004-03-25 |
CA2413417A1 (en) | 2002-01-03 |
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