JP7506473B2 - Amyloid β accumulation inhibitor - Google Patents
Amyloid β accumulation inhibitor Download PDFInfo
- Publication number
- JP7506473B2 JP7506473B2 JP2019230770A JP2019230770A JP7506473B2 JP 7506473 B2 JP7506473 B2 JP 7506473B2 JP 2019230770 A JP2019230770 A JP 2019230770A JP 2019230770 A JP2019230770 A JP 2019230770A JP 7506473 B2 JP7506473 B2 JP 7506473B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- amyloid
- general formula
- represented
- compound represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000007082 Aβ accumulation Effects 0.000 title claims description 56
- 239000003112 inhibitor Substances 0.000 title claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000004480 active ingredient Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 230000003925 brain function Effects 0.000 claims description 13
- 235000013305 food Nutrition 0.000 claims description 13
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 12
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000007423 decrease Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000003920 cognitive function Effects 0.000 claims description 8
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims description 6
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims description 6
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 6
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims description 6
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 6
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 6
- 229940045145 uridine Drugs 0.000 claims description 6
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 4
- 230000003405 preventing effect Effects 0.000 claims description 4
- 230000002554 disease preventive effect Effects 0.000 claims description 3
- 230000005750 disease progression Effects 0.000 claims description 3
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 claims 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 4
- 239000004129 EU approved improving agent Substances 0.000 claims 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims 4
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims 4
- 150000002148 esters Chemical class 0.000 claims 4
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims 2
- 235000021294 Docosapentaenoic acid Nutrition 0.000 claims 2
- 229930010555 Inosine Natural products 0.000 claims 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims 2
- 229910019142 PO4 Inorganic materials 0.000 claims 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims 2
- 229930003268 Vitamin C Natural products 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 2
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims 2
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims 2
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims 2
- 229960003786 inosine Drugs 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 235000021317 phosphate Nutrition 0.000 claims 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 2
- 229910052711 selenium Inorganic materials 0.000 claims 2
- 239000011669 selenium Substances 0.000 claims 2
- 229940104230 thymidine Drugs 0.000 claims 2
- 235000019154 vitamin C Nutrition 0.000 claims 2
- 239000011718 vitamin C Substances 0.000 claims 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 13
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 13
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 238000009825 accumulation Methods 0.000 description 8
- 125000004437 phosphorous atom Chemical group 0.000 description 7
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 5
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 230000037147 athletic performance Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 3
- 235000013928 guanylic acid Nutrition 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- VYIRVAXUEZSDNC-TXDLOWMYSA-N (3R,3'S,5'R)-3,3'-dihydroxy-beta-kappa-caroten-6'-one Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC(=O)[C@]1(C)C[C@@H](O)CC1(C)C VYIRVAXUEZSDNC-TXDLOWMYSA-N 0.000 description 2
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 2
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 2
- VYIRVAXUEZSDNC-LOFNIBRQSA-N Capsanthyn Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CC(O)CC2(C)C VYIRVAXUEZSDNC-LOFNIBRQSA-N 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102100039556 Galectin-4 Human genes 0.000 description 2
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 2
- UBORTCNDUKBEOP-UHFFFAOYSA-N L-xanthosine Natural products OC1C(O)C(CO)OC1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UHFFFAOYSA-N 0.000 description 2
- UBORTCNDUKBEOP-HAVMAKPUSA-N Xanthosine Natural products O[C@@H]1[C@H](O)[C@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-HAVMAKPUSA-N 0.000 description 2
- -1 alkali metal salts Chemical class 0.000 description 2
- WRANYHFEXGNSND-LOFNIBRQSA-N capsanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC(=O)C2(C)CCC(O)C2(C)C WRANYHFEXGNSND-LOFNIBRQSA-N 0.000 description 2
- 235000018889 capsanthin Nutrition 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000012658 paprika extract Nutrition 0.000 description 2
- 239000001688 paprika extract Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000003571 reporter gene assay Methods 0.000 description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 2
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 2
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 1
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- YKBGVTZYEHREMT-UHFFFAOYSA-N 2'-deoxyguanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1CC(O)C(CO)O1 YKBGVTZYEHREMT-UHFFFAOYSA-N 0.000 description 1
- LZSCQUCOIRGCEJ-FPKZOZHISA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one;hydrate Chemical compound O.C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 LZSCQUCOIRGCEJ-FPKZOZHISA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 235000017186 Celastrus paniculatus Nutrition 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- 240000003098 Embelia ribes Species 0.000 description 1
- 235000018436 Embelia ribes Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000015429 Mirabilis expansa Nutrition 0.000 description 1
- 244000294411 Mirabilis expansa Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108010052090 Renilla Luciferases Proteins 0.000 description 1
- 241000269851 Sarda sarda Species 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 1
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013527 bean curd Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- VGONTNSXDCQUGY-UHFFFAOYSA-N desoxyinosine Natural products C1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 VGONTNSXDCQUGY-UHFFFAOYSA-N 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- PVBRXXAAPNGWGE-LGVAUZIVSA-L disodium 5'-guanylate Chemical compound [Na+].[Na+].C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O PVBRXXAAPNGWGE-LGVAUZIVSA-L 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004226 guanylic acid Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 235000013536 miso Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000013555 soy sauce Nutrition 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、アミロイドβ蓄積抑制剤に関する。 The present invention relates to an agent for inhibiting amyloid β accumulation.
アミロイドβは、脳内で産生されるタンパク質の一つである。アミロイドβは、アルツハイマー病等の脳疾患において蓄積することが知られている。そのため、アミロイドβの蓄積を抑制するための組成物が種々検討されている。例えば、特許文献１には、ドコサヘキサエン酸とカプサンチン、又はドコサヘキサエン酸とカプサンチンとルテインとゼアキサンチンを含有する、内服組成物が記載されている。 Amyloid β is one of the proteins produced in the brain. It is known that amyloid β accumulates in brain diseases such as Alzheimer's disease. For this reason, various compositions for inhibiting the accumulation of amyloid β have been studied. For example, Patent Document 1 describes an oral composition containing docosahexaenoic acid and capsanthin, or docosahexaenoic acid, capsanthin, lutein, and zeaxanthin.
本発明者らは、特定の化合物がアミロイドβ蓄積抑制作用を示すことを見出した。本発明は、この新規な知見に基づくものであり、新規なアミロイドβ蓄積抑制剤を提供することを目的とする。 The inventors have found that certain compounds exhibit an inhibitory effect on amyloid β accumulation. The present invention is based on this novel finding, and aims to provide a novel inhibitor of amyloid β accumulation.
本発明は、下記一般式（１）で表される化合物及び下記一般式（２）で表される化合物並びにこれらの塩からなる群より選択される少なくとも１種を有効成分として含有する、アミロイドβ蓄積抑制剤に関する。
［一般式（１）中、Ｒ１１、Ｒ１２及びＲ１４は、それぞれ独立に、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基を表し、Ｒ１３は、下記式（３）～（６）で表される基からなる群から選択される基を表す。一般式（２）中、Ｒ２１は、水素原子又はアルキル基を表す。］
[In general formula (1), R 11 , R 12 and R 14 each independently represent a group selected from the group consisting of a phosphorus-containing group, a hydroxy group and a hydrogen atom, and R 13 represents a group selected from the group consisting of groups represented by the following formulas (3) to (6). In general formula (2), R 21 represents a hydrogen atom or an alkyl group.]
上記アミロイドβ蓄積抑制は、特定の化合物を有効成分として含有するため、アミロイドβ蓄積抑制作用を示す。 The above-mentioned amyloid β accumulation inhibition exhibits an amyloid β accumulation inhibition effect because it contains a specific compound as an active ingredient.
一態様において、アミロイドβ蓄積抑制剤は、上記一般式（１）で表される化合物又はその塩を有効成分として含有していてよい。 In one embodiment, the amyloid β accumulation inhibitor may contain the compound represented by the above general formula (1) or a salt thereof as an active ingredient.
一態様において、アミロイドβ蓄積抑制剤は、上記Ｒ１１、Ｒ１２及びＲ１４がヒドロキシ基であり、かつ上記Ｒ１３が上記式（３）～（６）で表される基からなる群から選択される基であってよい。 In one embodiment, the amyloid β accumulation inhibitor may be such that R 11 , R 12 and R 14 are hydroxy groups, and R 13 is a group selected from the group consisting of groups represented by formulas (3) to (6).
一態様において、アミロイドβ蓄積抑制剤は、上記Ｒ１１及びＲ１４がヒドロキシ基であり、上記Ｒ１２が水素原子であり、かつ上記Ｒ１３が前記式（３）で表される基であってよい。 In one embodiment, the amyloid β accumulation inhibitor may be such that R 11 and R 14 are hydroxy groups, R 12 is a hydrogen atom, and R 13 is a group represented by formula (3).
一態様において、アミロイドβ蓄積抑制剤は、上記Ｒ１１及びＲ１２がヒドロキシ基であり、上記Ｒ１４が下記式（７）で表される基であり、かつ上記Ｒ１３が上記式（３）で表される基であってよい。
一態様において、アミロイドβ蓄積抑制剤は、上記一般式（２）で表される化合物又はその塩を有効成分として含有していてよい。 In one embodiment, the amyloid β accumulation inhibitor may contain the compound represented by the above general formula (2) or a salt thereof as an active ingredient.
一態様において、アミロイドβ蓄積抑制剤は、上記Ｒ２１が水素原子であってよい。 In one embodiment, in the amyloid β accumulation inhibitor, R 21 may be a hydrogen atom.
一態様において、アミロイドβ蓄積抑制剤は、脳機能改善剤、脳機能低下防止剤、認知機能改善剤、記憶力改善剤、運動パフォーマンス改善剤、アルツハイマー病予防剤及びアルツハイマー病進行抑制剤からなる群から選択される少なくとも１種であってよい。 In one embodiment, the amyloid β accumulation inhibitor may be at least one selected from the group consisting of brain function improvers, brain function decline prevention agents, cognitive function improvers, memory improvers, exercise performance improvers, Alzheimer's disease preventive agents, and Alzheimer's disease progression inhibitors.
本発明はまた、下記一般式（１）で表される化合物及び下記一般式（２）で表される化合物並びにこれらの塩からなる群より選択される少なくとも１種を有効成分として含有する、アミロイドβ蓄積抑制用食品組成物に関する。
［一般式（１）中、Ｒ１１、Ｒ１２及びＲ１４は、それぞれ独立に、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基を表し、Ｒ１３は、下記式（３）～（６）で表される基からなる群から選択される基を表す。一般式（２）中、Ｒ２１は、水素原子又はアルキル基を表す。］
[In general formula (1), R 11 , R 12 and R 14 each independently represent a group selected from the group consisting of a phosphorus-containing group, a hydroxy group and a hydrogen atom, and R 13 represents a group selected from the group consisting of groups represented by the following formulas (3) to (6). In general formula (2), R 21 represents a hydrogen atom or an alkyl group.]
本発明によれば、新規なアミロイドβ蓄積抑制剤を提供することができる。 The present invention provides a novel agent for inhibiting amyloid β accumulation.
以下、本発明を実施するための形態について詳細に説明する。なお、本発明は、以下の実施形態に限定されるものではない。 The following describes in detail the embodiments of the present invention. Note that the present invention is not limited to the following embodiments.
（有効成分）
本実施形態に係るアミロイドβ蓄積抑制剤は、下記一般式（１）で表される化合物及び下記一般式（２）で表される化合物並びにこれらの塩からなる群より選択される少なくとも１種を有効成分として含有する。
(Active ingredient)
The amyloid β accumulation inhibitor of this embodiment contains, as an active ingredient, at least one selected from the group consisting of a compound represented by the following general formula (1), a compound represented by the following general formula (2), and salts thereof.
一般式（１）中、Ｒ１１、Ｒ１２及びＲ１４は、それぞれ独立に、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基を表し、Ｒ１３は、下記式（３）～（６）で表される基からなる群から選択される基を表す。一般式（２）中、Ｒ２１は、水素原子又はアルキル基を表す。 In general formula (1), R 11 , R 12 and R 14 each independently represent a group selected from the group consisting of a phosphorus-containing group, a hydroxy group and a hydrogen atom, and R 13 represents a group selected from the group consisting of groups represented by the following formulae (3) to (6): In general formula (2), R 21 represents a hydrogen atom or an alkyl group.
本実施形態に係るアミロイドβ蓄積抑制剤は、一般式（１）で表される化合物又はその塩を有効成分として含有していてよい。 The amyloid β accumulation inhibitor according to this embodiment may contain a compound represented by general formula (1) or a salt thereof as an active ingredient.
Ｒ１１は、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基であればよく、好ましくはヒドロキシ基である。 R 11 may be a group selected from the group consisting of a phosphorus atom-containing group, a hydroxy group, and a hydrogen atom, and is preferably a hydroxy group.
Ｒ１２は、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基であればよく、好ましくはヒドロキシ基又は水素原子である。 R 12 may be a group selected from the group consisting of a phosphorus atom-containing group, a hydroxy group, and a hydrogen atom, and is preferably a hydroxy group or a hydrogen atom.
Ｒ１３は、上記式（３）～（６）で表される基からなる群から選択される基であればよい。Ｒ３は、好ましくは上記式（３）又は（４）で表される基である。 R 13 may be a group selected from the group consisting of groups represented by the above formulas (3) to (6). R 3 is preferably a group represented by the above formula (3) or (4).
Ｒ１４は、リン原子を含む基、ヒドロキシ基及び水素原子からなる群より選択される基であればよく、好ましくはリン原子を含む基又はヒドロキシ基である。 R 14 may be a group selected from the group consisting of a group containing a phosphorus atom, a hydroxy group, and a hydrogen atom, and is preferably a group containing a phosphorus atom or a hydroxy group.
リン原子を含む基において、リン原子は、例えば１～３個であってよく、好ましくは１個である。リン原子を含む基は、好ましくは下記式（７）で表される基である。
一般式（１）で表される化合物は、アミロイドβ蓄積抑制作用の観点から、好ましくはＲ１１、Ｒ１２及びＲ１４がヒドロキシ基であり、かつＲ１３が式（３）～（６）で表される基からなる群から選択される基であるか、Ｒ１１及びＲ１４がヒドロキシ基であり、Ｒ１２が水素原子であり、かつＲ１３が式（３）で表される基であるか、又は、Ｒ１１及びＲ１２がヒドロキシ基であり、Ｒ１４が式（７）で表される基であり、かつＲ１３が式（３）で表される基であってよい。 From the viewpoint of the amyloid β accumulation inhibitory effect, the compound represented by general formula (1) may preferably be such that R 11 , R 12 and R 14 are hydroxy groups and R 13 is a group selected from the group consisting of groups represented by formulas (3) to (6), or R 11 and R 14 are hydroxy groups, R 12 is a hydrogen atom and R 13 is a group represented by formula (3), or R 11 and R 12 are hydroxy groups, R 14 is a group represented by formula (7) and R 13 is a group represented by formula (3).
Ｒ１１、Ｒ１２及びＲ１４がヒドロキシ基であり、かつＲ１３が式（３）～（６）で表される基である場合、一般式（１）で表される化合物は、それぞれ、グアノシン、キサントシン、シチジン及びウリジンと称されるものである。Ｒ１１及びＲ１４がヒドロキシ基であり、Ｒ１２が水素原子であり、かつＲ１３が式（３）で表される基である場合、一般式（１）で表される化合物は、２’－デオキシグアノシンと称されるものである。Ｒ１１及びＲ１２がヒドロキシ基であり、Ｒ１４が式（７）で表される基であり、かつＲ１３が式（３）で表される基である場合、一般式（１）で表される化合物は、グアニル酸（グアノシン一リン酸又はＧＭＰ）と称されるものである。 When R 11 , R 12 and R 14 are hydroxy groups and R 13 is a group represented by formulas (3) to (6), the compounds represented by general formula (1) are called guanosine, xanthosine, cytidine and uridine, respectively. When R 11 and R 14 are hydroxy groups, R 12 is a hydrogen atom and R 13 is a group represented by formula (3), the compound represented by general formula (1) is called 2'-deoxyguanosine. When R 11 and R 12 are hydroxy groups, R 14 is a group represented by formula (7) and R 13 is a group represented by formula (3), the compound represented by general formula (1) is called guanylic acid (guanosine monophosphate or GMP).
本実施形態に係るアミロイドβ蓄積抑制剤は、一般式（２）で表される化合物又はその塩を有効成分として含有していてよい。 The amyloid β accumulation inhibitor according to this embodiment may contain a compound represented by general formula (2) or a salt thereof as an active ingredient.
Ｒ２１は、水素原子又はアルキル基であればよい。Ｒ２１で示されるアルキル基の炭素数は、例えば１～３個であってよい。Ｒ２１で示されるアルキル基は、メチル基、エチル基又はプロピル基であってよく、直鎖状でも分岐状でもよい。Ｒ２１は、好ましくは水素原子である。この場合、一般式（２）で表される化合物は、グアニンと称されるものである。 R 21 may be a hydrogen atom or an alkyl group. The number of carbon atoms of the alkyl group represented by R 21 may be, for example, 1 to 3. The alkyl group represented by R 21 may be a methyl group, an ethyl group, or a propyl group, and may be linear or branched. R 21 is preferably a hydrogen atom. In this case, the compound represented by general formula (2) is called guanine.
一般式（１）で表される化合物及び一般式（２）で表される化合物は、塩としてアミロイドβ蓄積抑制剤に含まれていてもよい。塩としては、食品、医薬部外品又は医薬品として許容可能なものであれば特に制限されない。このような塩は、一般式（１）で表される化合物又は一般式（２）で表される化合物と無毒な塩を形成する塩基とにより形成されるものである。具体的には、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩等が挙げられる。一般式（１）で表される化合物及び一般式（２）で表される化合物の塩は、水和物であってもよい。 The compound represented by general formula (1) and the compound represented by general formula (2) may be contained in the amyloid β accumulation inhibitor as a salt. There are no particular limitations on the salt as long as it is acceptable as a food, quasi-drug, or pharmaceutical. Such a salt is formed by the compound represented by general formula (1) or the compound represented by general formula (2) and a base that forms a non-toxic salt. Specific examples include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. The salts of the compound represented by general formula (1) and the compound represented by general formula (2) may be hydrates.
本実施形態に係るアミロイドβ蓄積抑制剤は、有効成分として、一般式（１）で表される化合物及び一般式（２）で表される化合物並びにこれらの塩からなる群より選択される少なくとも１種を単独で含有していてもよく、２種以上を含有していてもよい。 The amyloid β accumulation inhibitor according to this embodiment may contain, as an active ingredient, at least one selected from the group consisting of a compound represented by general formula (1), a compound represented by general formula (2), and salts thereof, or may contain two or more of them.
本実施形態に係るアミロイドβ蓄積抑制剤は、アミロイドβ蓄積抑制作用を有する。アミロイドβは、アミロイド前駆体タンパク質（Ａｍｙｌｏｉｄβ Ｐｒｏｔｅｉｎ Ｐｒｅｃｕｒｓｏｒ、ＡＰＰ）がγセクレターゼという酵素で切断されることにより産生される。脳内でのアミロイドβの蓄積は、脳機能の悪化と関連する。そのため、γセクレターゼの活性を阻害することで、アミロイドβの蓄積が抑制されることにより、脳機能を改善し、また、脳機能の低下を予防することができる。この場合、本実施形態に係るアミロイドβ蓄積抑制剤は、脳機能改善剤又は脳機能低下防止剤ということもできる。 The amyloid β accumulation inhibitor according to this embodiment has an amyloid β accumulation inhibitory effect. Amyloid β is produced by cleavage of amyloid precursor protein (APP) by an enzyme called gamma secretase. Accumulation of amyloid β in the brain is associated with deterioration of brain function. Therefore, by inhibiting the activity of gamma secretase, the accumulation of amyloid β is suppressed, thereby improving brain function and preventing the decline of brain function. In this case, the amyloid β accumulation inhibitor according to this embodiment can also be called a brain function improver or a brain function decline preventer.
また、認知機能の低下、記憶力の低下、運動パフォーマンスの低下、アルツハイマー病の発症及びアルツハイマー病の進行においても、脳内においてアミロイドβが蓄積することがある。そのため、アミロイドβの蓄積を抑制することで、これらの症状を改善することができる。この場合、本実施形態に係るアミロイドβ蓄積抑制剤は、認知機能改善剤、記憶力改善剤、運動パフォーマンス改善剤、アルツハイマー病予防剤又はアルツハイマー病進行抑制剤ということもできる。 In addition, amyloid β may accumulate in the brain in the decline of cognitive function, decline of memory, decline of athletic performance, and the onset and progression of Alzheimer's disease. Therefore, these symptoms can be improved by inhibiting the accumulation of amyloid β. In this case, the amyloid β accumulation inhibitor according to this embodiment can also be called a cognitive function improving agent, a memory improving agent, an athletic performance improving agent, an Alzheimer's disease preventive agent, or an Alzheimer's disease progression inhibitor.
一般式（１）で表される化合物及び一般式（２）で表される化合物は、天然物（動物、植物、微生物等）に由来するものであっても、人為的に合成したものであってもよい。また、市販のものがあれば、それを使用してもよい。 The compound represented by general formula (1) and the compound represented by general formula (2) may be derived from natural products (animals, plants, microorganisms, etc.) or may be artificially synthesized. In addition, if a commercially available product is available, it may be used.
本実施形態に係るアミロイドβ蓄積抑制剤は、経口投与（経口摂取）されてもよく、非経口投与（非経口摂取）されてもよいが、経口投与（経口摂取）されることが好ましい。アミロイドβ蓄積抑制剤は、１日１回投与（摂取）されてもよく、１日複数回に分けて投与（摂取）されてもよい。 The amyloid β accumulation inhibitor according to this embodiment may be administered orally (ingested orally) or parenterally (ingested parenterally), but is preferably administered orally (ingested orally). The amyloid β accumulation inhibitor may be administered (ingested) once a day, or may be administered (ingested) in multiple divided doses per day.
本実施形態に係るアミロイドβ蓄積抑制剤が経口投与（経口摂取）される場合、経口投与量（経口摂取量）は、有効成分として、成人１日あたり、体重１ｋｇあたり例えば０．１ｍｇ～１ｇであってよく、好ましくは０．５～１００ｍｇであり、より好ましくは、１～４０ｍｇである。経口投与量（経口摂取量）は、個体の状態、年齢等に応じて適宜決定することができる。 When the amyloid β accumulation inhibitor according to this embodiment is orally administered (ingested), the oral dosage (oral intake) may be, for example, 0.1 mg to 1 g of active ingredient per kg of body weight per day for an adult, preferably 0.5 to 100 mg, and more preferably 1 to 40 mg. The oral dosage (oral intake) can be appropriately determined depending on the condition, age, etc. of the individual.
本実施形態に係るアミロイドβ蓄積抑制剤は、ヒトに投与（摂取）されても、非ヒト哺乳動物に投与されてもよい。 The amyloid β accumulation inhibitor of this embodiment may be administered (ingested) to humans or non-human mammals.
（その他成分）
本実施形態に係るアミロイドβ蓄積抑制剤は、上記有効成分のみからなるものであってもよく、またアミロイドβ蓄積抑制剤の具体的態様に応じて、上記有効成分の他、食品、医薬部外品又は医薬品に許容されるその他成分を含有するものであってもよい。
(Other ingredients)
The amyloid β accumulation inhibitor of this embodiment may consist only of the above-mentioned active ingredient, or, depending on the specific form of the amyloid β accumulation inhibitor, may contain, in addition to the above-mentioned active ingredient, other ingredients acceptable for use in foods, quasi-drugs, or pharmaceuticals.
（アミロイドβ蓄積抑制剤の形状）
本実施形態に係るアミロイドβ蓄積抑制剤は、固体、液体（溶液及び懸濁液を含む。）、ペースト等のいずれの形状であってもよい。また、本実施形態に係るアミロイドβ蓄積抑制剤は、例えば、錠剤（口腔内崩壊錠、チュアブル錠、フィルムコーティング錠等）、カプセル剤、散剤、顆粒剤、液剤（シロップ剤、ゼリー剤等）、軟膏剤、硬膏剤等のいずれの剤形であってもよい。
(Shape of amyloid β accumulation inhibitor)
The amyloid β accumulation inhibitor according to the present embodiment may be in any form, such as a solid, a liquid (including a solution and a suspension), a paste, etc. In addition, the amyloid β accumulation inhibitor according to the present embodiment may be in any form, such as a tablet (orally disintegrating tablet, chewable tablet, film-coated tablet, etc.), a capsule, a powder, a granule, a liquid (syrup, jelly, etc.), an ointment, a plaster, etc.
（アミロイドβ蓄積抑制剤の具体的態様）
本実施形態に係るアミロイドβ蓄積抑制剤は、例えば、食品組成物（飲料及び食品）、医薬部外品又は医薬品として調製することができる。飲料としては、例えば、水、清涼飲料水、果汁飲料、炭酸飲料、乳飲料、アルコール飲料、スポーツドリンク、栄養ドリンク等が挙げられる。食品としては、パン類、麺類、米類、豆腐、乳製品、醤油、味噌、菓子類等が挙げられる。また、食品組成物には、例えば、健康食品、機能性表示食品、特別用途食品、栄養補助食品、サプリメント及び特定保健用食品等が含まれる。
(Specific embodiment of amyloid β accumulation inhibitor)
The amyloid β accumulation inhibitor according to the present embodiment can be prepared, for example, as a food composition (beverage and food), a quasi-drug, or a pharmaceutical. Examples of beverages include water, soft drinks, fruit juice drinks, carbonated drinks, milk drinks, alcoholic drinks, sports drinks, and nutritional drinks. Examples of foods include bread, noodles, rice, tofu, dairy products, soy sauce, miso paste, and confectionery. Examples of food compositions include health foods, functional foods, special purpose foods, nutritional supplements, supplements, and foods for specified health uses.
本実施形態に係るアミロイドβ蓄積抑制剤は、日常的に手軽に摂取できることから、食品組成物（アミロイドβ蓄積抑制用食品組成物）であることが好ましい。本実施形態に係るアミロイドβ蓄積抑制用食品組成物の形態としては、上述したものが挙げられ、日常的に手軽に摂取できるという観点から、飲料（アミロイドβ蓄積抑制用飲料）であることが好ましい。 The amyloid β accumulation inhibitor according to this embodiment is preferably a food composition (food composition for inhibiting amyloid β accumulation) because it can be easily ingested on a daily basis. Examples of the form of the food composition for inhibiting amyloid β accumulation according to this embodiment include those described above, and from the viewpoint of easy daily intake, it is preferably a beverage (beverage for inhibiting amyloid β accumulation).
本実施形態のアミロイドβ蓄積抑制剤からなる、又はアミロイドβ蓄積抑制剤を含む上記製品は、脳機能改善用、脳機能低下防止用、認知機能改善用、記憶力改善用、運動パフォーマンス改善用、アルツハイマー病予防用又はアルツハイマー病進行抑制用であってよい。上記製品には、加齢によって低下する脳の血流や活動性を改善する旨、認知機能の一部である記憶の精度や判断の正確さを向上させる旨、認知機能の一部である記憶力を維持する旨、老化に伴うアミロイドβの蓄積を抑える旨、歩行能力の維持に役立つ等の表示が付されていてもよい。 The above-mentioned product consisting of the amyloid β accumulation inhibitor of this embodiment or containing the amyloid β accumulation inhibitor may be for improving brain function, preventing brain function decline, improving cognitive function, improving memory, improving exercise performance, preventing Alzheimer's disease, or suppressing the progression of Alzheimer's disease. The above-mentioned product may be labeled with the following: improving cerebral blood flow and activity that decline with age, improving memory accuracy and judgment accuracy, which are part of cognitive function, maintaining memory, which is part of cognitive function, suppressing accumulation of amyloid β associated with aging, helping to maintain walking ability, etc.
（アミロイドβ蓄積抑制剤の製法）
本実施形態に係るアミロイドβ蓄積抑制剤は、その具体的態様に応じて、例えば上述の有効成分を配合することで得ることができ、好ましくは上述の有効成分の有効量を含有するように調製することで得ることができる。このとき、有効成分である一般式（１）で表される化合物若しくは一般式（２）で表される化合物又はこれらの塩として、一般式（１）で表される化合物若しくは一般式（２）で表される化合物又はこれらの塩そのものを使用してもよいし、一般式（１）で表される化合物若しくは一般式（２）で表される化合物又はこれらの塩を含有する組成物（例えば、鰹節、魚肉等）を使用してもよく、澱粉を用いて発酵法によって製造したものを使用してもよい。
(Method for producing an amyloid β accumulation inhibitor)
The amyloid β accumulation inhibitor according to the present embodiment can be obtained by, for example, mixing the above-mentioned active ingredients according to its specific embodiment, and can be preferably obtained by preparing it so as to contain an effective amount of the above-mentioned active ingredients. At this time, as the active ingredient, the compound represented by general formula (1) or the compound represented by general formula (2) or a salt thereof, the compound represented by general formula (1) or the compound represented by general formula (2) or a salt thereof may be used as it is, or a composition containing the compound represented by general formula (1) or the compound represented by general formula (2) or a salt thereof (for example, dried bonito, fish meat, etc.), or a product produced by fermentation using starch may be used.
（作用効果）
本実施形態に係るアミロイドβ蓄積抑制剤は、一般式（１）で表される化合物及び一般式（２）で表される化合物並びにこれらの塩からなる群より選択される少なくとも１種を有効成分として含有するものであることから、当該アミロイドβ蓄積抑制剤を投与（摂取）することにより、アミロイドβの蓄積を抑制することができる。また、アミロイドβの蓄積を抑制する結果、脳機能を改善し、脳機能の低下を防止し、認知機能を改善し、記憶力を改善し、運動パフォーマンスを改善し、アルツハイマー病を予防し、又はアルツハイマー病の進行を抑制することができる。
(Action and Effect)
The amyloid β accumulation inhibitor according to the present embodiment contains at least one selected from the group consisting of a compound represented by general formula (1) and a compound represented by general formula (2) and salts thereof as an active ingredient, and thus administration (ingestion) of the amyloid β accumulation inhibitor can inhibit the accumulation of amyloid β. Furthermore, as a result of inhibiting the accumulation of amyloid β, it is possible to improve brain function, prevent the decline of brain function, improve cognitive function, improve memory, improve athletic performance, prevent Alzheimer's disease, or inhibit the progression of Alzheimer's disease.
以下、実施例に基づいて本発明をより具体的に説明する。ただし、本発明は、以下の実施例により限定されるものではない。 The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples.
＜試験例１：アミロイドβ蓄積抑制作用の評価＞
表１に示す化合物のアミロイドβ蓄積抑制作用を、レポータージーンアッセイにより評価した。具体的な方法は、以下のとおりである。
<Test Example 1: Evaluation of inhibitory effect on amyloid β accumulation>
The amyloid β accumulation inhibitory effect of the compounds shown in Table 1 was evaluated by a reporter gene assay. The specific method is as follows.
（ベクターの作製及び遺伝子導入）
アミロイドβの前駆体であるＡＰＰのＣ末端側１００残基分に、ＧＡＬ４のＤＮＡ結合領域と単純ヘルペスウイルスの転写活性化領域とを融合したＧＡＬ４－ＶＰ１６（Ｇ４Ｖ１６）を付加した蛋白質（ＡＰＰ－Ｇ４Ｖ１６）を発現させるベクターを構築した。ルシフェラーゼ発現ベクターは、ホタルルシフェラーゼ発現ベクターｐＧＬ４．３５（Ｐｒｏｍｅｇａ社製）、及び、内部標準としてウミシイタケルシフェラーゼ発現ベクターｐＧＬ４．７４（Ｐｒｏｍｅｇａ社製）を使用した。
(Vector Construction and Gene Transfer)
A vector was constructed to express a protein (APP-G4V16) in which GAL4-VP16 (G4V16), which is a fusion of the DNA binding domain of GAL4 and the transcription activation domain of herpes simplex virus, was added to the C-terminal 100 residues of APP, the precursor of amyloid β. The luciferase expression vector used was firefly luciferase expression vector pGL4.35 (Promega), and Renilla luciferase expression vector pGL4.74 (Promega) was used as an internal standard.
１００ｍｍディッシュにＨＥＫ２９３細胞を１５０万個／ディッシュで播種し、ＤＭＥＭ培地（ＳＩＧＭＡ-ＡＬＤＲＩＣＨ社製）中で１日培養した。その後、ＯＰＴＩ－ＭＥＭ培地（Ｔｈｅｒｍｏ ＦＩＳＨＥＲ社製）に培地交換後、ＯＰＴＩ－ＭＥＭ５００μＬに、ＡＰＰ－Ｇ４Ｖ１６発現ベクター１μｇ、プロモーター領域にＧＡＬ４認識配列（ＵＡＳ）を９個挿入したルシフェラーゼのレポーター（ｐＧＬ４．３５）１μｇ、及び内部標準ベクターｐＧＬ４．７４（Ｐｒｏｍｅｇａ社製）０．５μｇを混合し、Ｌｉｐｏｆｅｃｔａｍｉｎｅ３０００（Ｔｈｅｒｍｏ ＦＩＳＨＥＲ社製）を用いてＨＥＫ２９３細胞に添加して遺伝子導入し、３時間培養した。遺伝子導入後、細胞を回収し、ＤＭＥＭ培地で９６ｗｅｌｌプレートに１０００個／ｗｅｌｌで播種した。直ちに、表１に示された化合物（濃度：２０μＭ）を添加し、２４時間後に細胞を回収した。なお、コントロール（ＣＮＴ）として、試薬溶媒を添加した時の測定値を用いた。 HEK293 cells were seeded in a 100 mm dish at 1.5 million cells/dish and cultured in DMEM medium (SIGMA-ALDRICH) for one day. After that, the medium was replaced with OPTI-MEM medium (Thermo FISHER), and 1 μg of APP-G4V16 expression vector, 1 μg of luciferase reporter (pGL4.35) with nine GAL4 recognition sequences (UAS) inserted in the promoter region, and 0.5 μg of internal standard vector pGL4.74 (Promega) were mixed in 500 μL of OPTI-MEM, and added to HEK293 cells using Lipofectamine3000 (Thermo FISHER) for gene transfer and cultured for 3 hours. After gene transfer, the cells were collected and seeded in DMEM medium at 1000 cells/well on a 96-well plate. Immediately, the compounds shown in Table 1 (concentration: 20 μM) were added, and the cells were collected 24 hours later. As a control (CNT), the measured value when the reagent solvent was added was used.
（レポータージーンアッセイ）
細胞内のルシフェラーゼ活性を、Ｄｕａｌ－Ｌｕｃｉｆｅｒａｓｅ ＲｅｐｏｒｔｅｒＡｓｓａｙ Ｓｙｓｔｅｍ（Ｐｒｏｍｅｇａ社製）を用いて測定した。ルシフェラーゼの発光は、ルミノメーター（Ｐｒｏｍｅｇａ社製）を用いて定量した。結果を表１に示す。表１における相対ルシフェラーゼ活性量は、コントロールのルシフェラーゼ活性に対する値を示す。
(Reporter Gene Assay)
Intracellular luciferase activity was measured using a Dual-Luciferase Reporter Assay System (Promega). Luciferase luminescence was quantified using a luminometer (Promega). The results are shown in Table 1. The relative luciferase activity in Table 1 indicates the value relative to the luciferase activity of the control.
表１に示すとおり、グアノシン、シチジン、ウリジン、キサントシン・２Ｈ２Ｏ、グアニン、２’－デオキシグアノシン一水和物及びグアノシン－５’－一リン酸二ナトリウムは、アミロイドβの蓄積を抑制することが示された。
As shown in Table 1, it was shown that guanosine, cytidine, uridine, xanthosine·2H 2 O, guanine, 2′-deoxyguanosine monohydrate and disodium guanosine-5′-monophosphate inhibit the accumulation of amyloid β.
Claims (7)
［一般式（１）中、Ｒ１１、Ｒ１２及びＲ１４は、それぞれ独立に、下記式（７）で表される基、ヒドロキシ基及び水素原子からなる群より選択される基を表し、Ｒ１３は、下記式（３）及び（５）～（６）で表される基からなる群から選択される基を表す。但し、Ｒ １３ が、式（３）で表される基である場合、Ｒ １４ は、式（７）で表される基である。一般式（２）中、Ｒ２１は、水素原子又はアルキル基を表す。］
[In general formula (1), R 11 , R 12 and R 14 each independently represent a group selected from the group consisting of a group represented by the following formula (7) , a hydroxy group and a hydrogen atom, and R 13 represents a group selected from the group consisting of groups represented by the following formulas (3) and (5) to (6). However, when R 13 is a group represented by formula (3), R 14 is a group represented by formula (7). In general formula (2), R 21 represents a hydrogen atom or an alkyl group.]
［一般式（１）中、Ｒ１１、Ｒ１２及びＲ１４は、それぞれ独立に、下記式（７）で表される基、ヒドロキシ基及び水素原子からなる群より選択される基を表し、Ｒ１３は、下記式（３）及び（５）～（６）で表される基からなる群から選択される基を表す。但し、Ｒ １３ が、式（３）で表される基である場合、Ｒ １４ は、式（７）で表される基である。一般式（２）中、Ｒ２１は、水素原子又はアルキル基を表す。］
A food composition for inhibiting amyloid β accumulation, comprising as an active ingredient at least one selected from the group consisting of a compound represented by the following general formula (1) and a compound represented by the following general formula (2) , and salts thereof (excluding those containing (i) one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof, (ii) at least one of docosahexaenoic acid (22:6, DHA), eicosapentaenoic acid (20:5, EPA) and docosapentaenoic acid (22:5, DPA), or esters thereof, and (iii) vitamin C and/or selenium, and excluding those containing nucleic acid components consisting of inosine, cytidine, 5'-guanosine-n'-monophosphate, uridine and thymidine, and/or pharmacologically acceptable salts thereof) .
[In general formula (1), R 11 , R 12 and R 14 each independently represent a group selected from the group consisting of a group represented by the following formula (7) , a hydroxy group and a hydrogen atom, and R 13 represents a group selected from the group consisting of groups represented by the following formulas (3) and (5) to (6). However, when R 13 is a group represented by formula (3), R 14 is a group represented by formula (7). In general formula (2), R 21 represents a hydrogen atom or an alkyl group.]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019230770A JP7506473B2 (en) | 2019-12-20 | 2019-12-20 | Amyloid β accumulation inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019230770A JP7506473B2 (en) | 2019-12-20 | 2019-12-20 | Amyloid β accumulation inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2021098665A JP2021098665A (en) | 2021-07-01 |
| JP7506473B2 true JP7506473B2 (en) | 2024-06-26 |
Family
ID=76540750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019230770A Active JP7506473B2 (en) | 2019-12-20 | 2019-12-20 | Amyloid β accumulation inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP7506473B2 (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020040031A1 (en) | 2000-07-07 | 2002-04-04 | Glasky Michelle S. | Methods for prevention of accumulation of amyloid beta peptide in the central nervous system |
| JP2009242431A (en) | 2009-07-17 | 2009-10-22 | Snow Brand Milk Prod Co Ltd | Prophylactic-ameliorative-therapeutic agent for dysbolism caused by aging |
| JP2010507666A (en) | 2006-10-25 | 2010-03-11 | ザ ロックフェラー ユニヴァーシティ | Methods and compositions for the treatment of Aβ related disorders |
| CN102429906A (en) | 2010-09-29 | 2012-05-02 | 国家纳米科学中心 | Application of nitrogen heterocyclic compound in preparation of drugs for inhibiting toxicity of amyloid polypeptide |
| JP2013053076A (en) | 2011-09-01 | 2013-03-21 | Kyoto Univ | Alzheimer's disease preventive agent |
| JP2015030673A (en) | 2013-07-31 | 2015-02-16 | 奥野製薬工業株式会社 | Amyloid beta peptide inhibitors |
| JP2019512488A (en) | 2016-03-08 | 2019-05-16 | エヌ．ブイ．・ヌートリシア | Method for treating brain atrophy |
| JP2019529472A (en) | 2016-09-26 | 2019-10-17 | タフツ・ユニバーシティ | Uridine nucleoside derivatives, compositions and methods of use |
-
2019
- 2019-12-20 JP JP2019230770A patent/JP7506473B2/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020040031A1 (en) | 2000-07-07 | 2002-04-04 | Glasky Michelle S. | Methods for prevention of accumulation of amyloid beta peptide in the central nervous system |
| JP2010507666A (en) | 2006-10-25 | 2010-03-11 | ザ ロックフェラー ユニヴァーシティ | Methods and compositions for the treatment of Aβ related disorders |
| JP2009242431A (en) | 2009-07-17 | 2009-10-22 | Snow Brand Milk Prod Co Ltd | Prophylactic-ameliorative-therapeutic agent for dysbolism caused by aging |
| CN102429906A (en) | 2010-09-29 | 2012-05-02 | 国家纳米科学中心 | Application of nitrogen heterocyclic compound in preparation of drugs for inhibiting toxicity of amyloid polypeptide |
| JP2013053076A (en) | 2011-09-01 | 2013-03-21 | Kyoto Univ | Alzheimer's disease preventive agent |
| JP2015030673A (en) | 2013-07-31 | 2015-02-16 | 奥野製薬工業株式会社 | Amyloid beta peptide inhibitors |
| JP2019512488A (en) | 2016-03-08 | 2019-05-16 | エヌ．ブイ．・ヌートリシア | Method for treating brain atrophy |
| JP2019529472A (en) | 2016-09-26 | 2019-10-17 | タフツ・ユニバーシティ | Uridine nucleoside derivatives, compositions and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| TAROZZI, A. et al.，Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by Amyloid-β peptide oligomers，Journal of Biological Regulators & Homeostatic Agents，2010年，Vol.24, No.3，pp. 297-306 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2021098665A (en) | 2021-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2754444B1 (en) | Composition for improving in vivo metabolism parameter | |
| ES2585066T3 (en) | Compositions for the treatment of neurological disorders | |
| US20120252768A1 (en) | Composition containing protopanaxatriol and protopanaxadiol | |
| JP7506473B2 (en) | Amyloid β accumulation inhibitor | |
| JP6830976B2 (en) | MicroRNA expression enhancer and food and drink for microRNA expression enhancer | |
| ES2964978T3 (en) | 10-Hydroxy-cis-12-octadecenoic acid alkyl ester and its use | |
| WO2020262114A1 (en) | Mitochondrial function activator | |
| JP2007230973A (en) | Composition having anticancer activity action | |
| WO2023089986A1 (en) | Compound, racemate of said compound, salt of said compound or said racemate, composition, anti-inflammatory agent, therapeutic agent for dementia, and therapeutic agent for rett syndrome | |
| US20200170269A1 (en) | Allulose-containing composition for promoting excretion of vegetable lipids from the body | |
| JP6017330B2 (en) | Preventive or ameliorating agent for overactive bladder | |
| JP7356692B2 (en) | Myoblast proliferation promoter and muscle strengthening agent | |
| JP6391959B2 (en) | Non-alcoholic steatohepatitis ameliorating agent and ameliorating nutrition composition | |
| WO2023167252A1 (en) | Bdnf production promoter | |
| JP2009126830A (en) | Therapeutic agent | |
| JPWO2019022149A1 (en) | Ketone body formation accelerator | |
| WO2021255979A1 (en) | Anti-obesity composition and composition for oral administration | |
| JP6903367B1 (en) | Anti-obesity composition and oral composition | |
| JP2011241195A (en) | Ucp-1 production promoter, ucp-2 production promoter, fat combustion promoter, and fat accumulation inhibitor | |
| US20240115589A1 (en) | Pharmaceutical composition for preventing cytokine storm | |
| JP2014152118A (en) | Aging retardant | |
| JP2021046375A (en) | β3 ADRENERGIC RECEPTOR AGONIST | |
| JP7371851B2 (en) | Composition containing oleanane-type triterpene that prevents or improves physical fatigue and feeling of fatigue | |
| JP5546854B2 (en) | Damamaran triterpene-containing food and beverage composition and method for improving taste | |
| NL1036427C2 (en) | Activators of the autophagic pathway. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20201007 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20221213 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240123 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240322 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240604 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240614 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7506473 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |