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WO2023202102A1 - Utilisation d'un composé sesquiterpénoïde dans l'inhibition de l'activité du canal trpa1 - Google Patents

Utilisation d'un composé sesquiterpénoïde dans l'inhibition de l'activité du canal trpa1 Download PDF

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WO2023202102A1
WO2023202102A1 PCT/CN2022/138608 CN2022138608W WO2023202102A1 WO 2023202102 A1 WO2023202102 A1 WO 2023202102A1 CN 2022138608 W CN2022138608 W CN 2022138608W WO 2023202102 A1 WO2023202102 A1 WO 2023202102A1
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pain
compound
diseases
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王树
刘荆婧
贺冬梅
陈飞裕
张文杰
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广州医科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to the field of biomedicine technology, and in particular to an antagonist of the transient receptor potential (TRP) ion channel family. Specifically, the present invention relates to the application of sesquiterpenoids in inhibiting the activity of the TRPAl channel.
  • TRP transient receptor potential
  • TRP channels are a type of ion channel widely present in mammals. This family is divided into seven subfamilies, namely TRPC, TRPV, TRPM, TRPN, TRPML, TRPA and TRPP. TRP channels are all six-transmembrane proteins, with both their N-terminal and C-terminal ends inside the cell. The fifth and sixth transmembrane domains together form a non-selective cation channel. These channels usually serve as receptors for a variety of chemical and physical stimuli and can be regulated by many factors, including temperature, osmotic pressure, pH, mechanical force, as well as some endogenous and exogenous ligands and intracellular signaling molecules.
  • the TRPA1 channel is a member of the transient receptor potential channel family. It has at least 14 ankyrin repeat sequences at its N-terminus. It is also called ankyrin-like protein with transmembrane domain protein 1 (ANKTM1) and is widely distributed in lactation.
  • ANKTM1 transmembrane domain protein 1
  • the former mainly include sensory neurons of the peripheral nervous system such as trigeminal ganglia, dorsal root ganglia and vagus ganglia, while the latter include vascular endothelial cells, pancreatic islet cells, cardiomyocytes, inner ear hair cells, Hepatocytes, gastrointestinal mucosa, pancreatic cells, renal epithelial cells, prostate epithelial cells, breast cells, B lymphocytes, T lymphocytes, lung fibroblasts, melanocytes, dental pulp fibroblasts, mast cells and enterochromaffin cells and keratinocytes, etc.
  • the peripheral nervous system such as trigeminal ganglia, dorsal root ganglia and vagus ganglia
  • the latter include vascular endothelial cells, pancreatic islet cells, cardiomyocytes, inner ear hair cells, Hepatocytes, gastrointestinal mucosa, pancreatic cells, renal epithelial cells, prostate epithelial cells, breast cells, B lymph
  • the TRPA1 channel is a ligand-dependent non-selective cation conduction channel. It undergoes structural changes by binding to specific ligands. The channel opens and cations such as calcium ions, sodium ions, and potassium ions flow into the cell, which affects the cell membrane. The regulation of electric potential is of great significance to maintaining the normal physiological functions of the body.
  • This channel is generally considered to be a sensor of various senses (pain, cold, mechanical, itching, vision, smell, hearing, etc.) in humans and other mammals, and also serves as a stimulus to elicit protective responses (tears, airway resistance, and coughing). ) sensor, and studies over the past few years have found that this receptor is also involved in inflammation and immune responses.
  • TRPA1 channels In addition to physiological functions, TRPA1 channels also play an important role in pathological processes in various systems of humans and animals, including pain and inflammation, pruritus, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiac diseases, etc. Various pathological processes such as vascular diseases and skin diseases.
  • TRPA1 channels Activation of TRPA1 channels plays an important role in the generation and enhancement of pain. This channel is widely involved in nociceptive pain, neuropathic pain, cancer pain, dysfunctional pain, migraine, trigeminal neuralgia, inflammatory pain, and chronic pain. Wait for the occurrence and development of various types of pain. Activation of TRPA1 plays a major role in the rapid onset and maintenance of inflammation. Many endogenous TRPA1 agonists are produced during inflammation. Activation of TRPA1 can lead to vasodilation, a major symptom of inflammatory tissue. At the same time, activation of TRPA1 in epidermal keratinocytes enhanced the expression of known pro-inflammatory cytokines, which are key factors in skin inflammation.
  • TRPA1 Such as inflammation caused by atopic dermatitis, allergic dermatitis, otitis media, acne, acne, rosacea and other diseases. Itch is associated with TRPA1 activation, including histamine-dependent and histamine-independent itch. Literature suggests that activation of TRPA1 is closely related to pruritus caused by contact dermatitis, atopic dermatitis (AD), allergic dermatitis, and lymphoma. TRPA1 is widely distributed in the gastrointestinal cell network and is believed to be involved in gastrointestinal inflammation (such as idiopathic inflammatory bowel disease, IBD) and its pain response mechanism.
  • IBD idiopathic inflammatory bowel disease
  • TRPA1 may be a target for the treatment of stress visceral hyperalgesia in irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • TRPA1 antagonists or deletion of the TRPA1 gene can reduce pancreatic inflammation, while inflammatory mediators that activate TRPA1 can increase pancreatic inflammation and pain.
  • TRPA1 not only plays an important role in normal airway function, but is particularly important in respiratory diseases characterized by allergies, such as asthma, rhinitis, chronic obstructive pulmonary disease (COPD), bronchitis, and chronic cough.
  • TRPA1 channels are abundant in the cells of the lower urinary tract of animals, so TRPA1 is considered to have a regulatory effect on the urinary system.
  • TRPA1 may play an important role in the regulation of bladder contraction, and TRPA1 antagonists can reduce overactive bladder (OAB) symptoms and reduce the micturition reflex.
  • OAB overactive bladder
  • TRPA1 substance P and CGRP were co-expressed in bladder nerve terminals, suggesting that TRPA1 plays an important role in inflammatory cystitis.
  • Peripheral diabetic neuropathy (PDN) is a complication of diabetes, and TRPA1 activation at nerve fiber terminals may be a mechanism leading to this complication.
  • TRPA1-mediated mechanism is involved in the occurrence and development of diabetic cardiomyopathy. People are still learning more about the function and role of the TRPA1 channel, and the latest research has found that its antagonists have antidepressant and anxiolytic effects.
  • TRPA1 channels can be activated by many chemical or physical factors, including electrophilic agonists, non-electrophilic agonists, natural compounds, calcium ions, metal ions, pH, hot and cold stimuli, light, polyphosphates, and phosphorylation modifications wait.
  • electrophilic agonists Non-electrophilic agonists
  • non-electrophilic agonists natural compounds
  • calcium ions calcium ions
  • metal ions calcium ions
  • pH hot and cold stimuli
  • light polyphosphates
  • phosphorylation modifications wait.
  • Classic antagonists include HC-030031, GRC17536, A-967079, ALGX-2513, ALGX-2541, ALGX-2563, ALGX-2561, ALGX-2542, etc.
  • TRPA1 plays an important role in pain, inflammation, and potential indications for many other acquired diseases. Many TRPA1 agonists have been shown to cause pain, irritation, inflammation, and worsen disease symptoms in humans and animals. It is expected that TRPA1 antagonists may be used in As they play a therapeutic role in related diseases, the market demand for TRPA1 antagonists will also steadily increase. Although research on TRPA1 channel-related diseases has made great progress in the past decade, many TRPA1 agonists have been discovered, but there are only a few antagonists, and only 5 have entered clinical trials, and almost none will be used in clinical trials. Preclinical results translate into clinical practice, and research on these antagonists is currently at a standstill. There are currently few new treatments available to patients, and older drugs have considerable side effects and incomplete efficacy. For these reasons, patients are often undertreated and there is a clear need for new, safer and more effective TRPA1 antagonists.
  • the object of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an application of sesquiterpenoids in inhibiting the activity of TRPA1 channels.
  • the first object of the present invention is to provide the use of a compound, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, which is characterized in that it is used for the preparation of medicines or Preparations, the drugs or preparations are used for: (a) inhibiting the activity of TRPAl channels; (b) treating diseases related to TRPAl channels;
  • Sesquiterpenes are a type of terpene composed of three isoprene units, and their molecular formula is usually C 15 H 24 . Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical changes such as oxidation or rearrangement produce related sesquiterpenes. Sesquiterpenes occur naturally in plants and insects and are signaling chemicals such as defense agents or pheromones. Plants, fungi and animals produce a range of different sesquiterpenes that can effectively modulate the activity of TRPA1 channels in response to external stimuli.
  • the compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.
  • the R1, R10 and R15 are selected from CH 3 ;
  • R2 is selected from -OH
  • R3 is selected from COOH;
  • the diseases include at least one of pain, inflammation, itching, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiovascular diseases, and skin diseases. kind.
  • the pain includes chronic pain, neuropathic pain, acute pain, inflammatory pain, post-herpetic pain, neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy , nerve damage, rheumatoid arthritis pain, osteoarthritis pain, back pain, lumbago, cancer pain, toothache, headache, migraine, trigeminal neuralgia, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica , at least one of pelvic allergy, pelvic pain, menstrual pain, visceral pain, and postoperative pain; the inflammation includes burns or osteoarthritis; the neurological disease includes neurological disorders induced by anticancer agents;
  • the gastrointestinal disease includes at least one of functional gastrointestinal disease, reflux esophagitis, ulcer, inflammatory bowel disease, vomiting, and pancreatitis; the functional gastrointestinal disease includes swallowing disorder, irritable bowel syndrome and functional abdominal pain syndrome; the urinary system diseases include at least one of overactive bladder,
  • the diseases include chronic pain, neuropathic pain, acute pain, asthma, chronic obstructive pulmonary disease, functional gastrointestinal disease, reflux esophagitis, inflammatory bowel disease, pruritus, anticancer agent-induced at least one of the neurological disorders.
  • the medicine contains 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% of the compound of formula (I), or its optical isomer or its The racemate, or its solvate, or its pharmaceutically acceptable salt, based on the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which includes compounds as used in the above applications and other drugs that can inhibit the activity of TRPAl channels.
  • Other drugs that can inhibit the activity of TRPA1 channels include HC-030031, A-967079, AP-18, PF-04745637, Chembridge-5861528, etc.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all substances that are compatible with the administration of the drug, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and Other substances and compounds. Except to the extent that a conventional media or agent is incompatible with the active compound, its use in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Useful carriers for preparing compositions thereof may be solid, liquid or gaseous; thus, the compositions may be in the form of tablets, pills, capsules, suppositories, powders, enteric-coated or otherwise protected formulations (e.g. combined with in the form of ion exchange resin or packaged in lipoprotein vesicles), sustained-release preparations, solutions, suspensions, elixirs, aerosols, etc.
  • the carrier may be selected from different oils, including petroleum, animal oils, vegetable oils or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, especially (when isotonic with blood) for injectable solutions.
  • formulations for intravenous administration include sterile aqueous solutions of the active ingredient, which are prepared by dissolving the solid active ingredient in water to produce an aqueous solution, and rendering the solution sterile.
  • suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, chlorine Sodium chloride, anhydrous skim milk, glycerin, propylene glycol, water, ethanol, etc.
  • compositions will contain an effective amount of the active compound, together with a suitable carrier to prepare a suitable dosage form for appropriate administration to the recipient.
  • the compounds of the invention may be administered in any suitable manner, such as oral (eg, buccal), topical, sublingual, rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and intrathecal Extramembranous and intranasal and, if necessary for local treatment, intralesional administration.
  • Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.
  • the present invention has the following beneficial effects:
  • the medicine of the present invention includes specific sesquiterpene compounds, which can significantly inhibit the activity of TRPAl channel.
  • the compound of formula (I) has a good inhibitory effect on TRPA1 channels and can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders), itching, and skin diseases (acne, pimples) related to TRPA1 targets. ), urinary tract disorders, inflammatory bowel disease, etc.
  • Figure 1 is a diagram showing compound A’s inhibition of TRPA1 current activated by AITC in hTRPA1-HEK293;
  • Figure 2 is a concentration-response curve generated by the TRPA1 agonist AITC and compound A in hTRPA1-HEK293;
  • Figure 3 is a diagram showing the influence of each group in Example 2 on the mechanical pain threshold of CFA-induced model group mice;
  • Figure 4 is a graph showing the results of scratching times in 1 hour for each group in the SADBE-induced mouse chronic itch model in Example 3;
  • Figure 5 is a graph showing the results of the number of coughs of each group in the rat variant asthma model in Example 4.
  • the present invention relates to patch clamp technology, which is a technology that records the ion current of ion channels to reflect the activities of single (or multiple) ion channel molecules on the cell membrane.
  • patch clamp technology is a technology that records the ion current of ion channels to reflect the activities of single (or multiple) ion channel molecules on the cell membrane.
  • Whole-cell patch clamp technology was used to verify whether compound A plays an antagonistic role in TRPA1 channel.
  • the structure of compound A is:
  • HEK293 cells purchased from Invitrogen.
  • cell culture medium DMEM Gibco BRL, Invitrogen
  • penicillin/streptomycin 5 ⁇ 10 6 IU/L, Gibco
  • 10% fetal calf serum Hyclone, Logan UT, USA
  • 12-well cell culture plate, 24-well cell culture plate and 3.5cm cell culture dish Corning
  • LipoD293 in vitro DNA transfection reagent (1ml, SignaGen)
  • NaCl 500g, Sigma
  • MgCl 500g, Sigma
  • EGTA 500g, Sigma
  • HEPES (1g, Macklin
  • AITC (1g, Sigma).
  • HEK293 cells were cultured in DMED cell culture medium containing 0.05g/L streptomycin, 0.05g/L penicillin, and 10% fetal calf serum, and placed in a constant temperature incubator at 37°C, 5% CO2, and saturated humidity. nourish.
  • 2.2 Cell transfection Use LipoD293 in vitro DNA transfection reagent to transiently transfect hTRA1 channel and EGFP plasmid into HEK293 cells. After 24 hours, observe the transfection efficiency and cell status under a 10X fluorescence microscope. If both are acceptable, resuspend the cells and transfer them to a 3.5cm cell culture dish and use them within 48 hours.
  • compound A can inhibit the TRPA1 current activated by AITC in hTRPA1-HEK293.
  • the half inhibitory concentration is 4.242 ⁇ M.
  • Each point represents the mean ⁇ S.E.M., n>10 cells.
  • Preparation of compound A solution Use DMSO with a concentration of 30% as a solvent to prepare a compound A solution with a concentration of 1 mg/ml, then dilute it with physiological saline to a concentration of 100umol/L and store it in a 4°C refrigerator for later use.
  • HC-030031 solution Use DMSO with a concentration of 30% as a solvent to prepare a HC-030031 solution with a concentration of 10 mg/ml, then dilute it with physiological saline to a solution with a concentration of 300 ⁇ mol/L and store it in a 4°C refrigerator for later use.
  • Preparation of CFA solution and Tween-80 solution After uniformly mixing 20ul of Tween-80 and 180ul of physiological saline, add 800ul of CFA, mix evenly on a vortex mixer to form a CFA solution, and place it at 4°C Store in the refrigerator for later use; mix 20ul of Tween-80 and 980ul of physiological saline evenly, prepare a Tween-80 solution, and store it in a 4°C refrigerator for later use.
  • mice Twelve C57BL/6J mice, 6-8 weeks old, male, weighing 20-25g, were randomly divided into four groups.
  • Normal group CFA group, CFA+Compound A group (100umol/L), CFA+HC-030031 (300umol/L) positive control group.
  • CFA group CFA+Compound A group (100umol/L)
  • CFA+HC-030031 300umol/L positive control group.
  • mice's spontaneous activity decreased, and there was obvious redness and swelling in the right hind foot compared with the left hind foot, which was different from normal. Compared with the group, the activity behavior was significantly reduced, indicating that the modeling was successful.
  • the normal group and CFA model group were gavaged with double-distilled water, and the CFA+ administration group was gavaged with the above concentrations of Compound A and HC-03003150ul respectively, and the mechanical stimulation pain threshold was measured.
  • mice C57BL/6J mice 6-8 weeks old, male 20-25g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008.
  • Animal breeding environment temperature (24+2)°C, relative humidity 50% to 70%, and 12h:12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
  • mice After 1 week of adaptive feeding, 18 mice were selected and divided into blank group, model control group, dexamethasone group and compound A low (1mg/kg), medium (5mg/kg) and high dose (10mg/kg) using random number table method. kg) groups, 3 animals in each group. Two days before the experiment, the hair on the back of the mouse's neck was shaved, with an area of approximately 2cmx3cm. Except for the blank group, other groups applied 20 ⁇ L of 0.5% SADBE acetone topically to the shaved abdominal skin of mice for sensitization once a day for three consecutive days.
  • mice After 5 days, 20 ⁇ L of 0.5% SADBE in acetone was topically applied to the shaved neck skin of mice once a day for three consecutive days. One day later, the low, medium and dose groups of Compound A were applied to the back skin of mice once a day by subcutaneous injection for 3 consecutive days. The mice in the control group were injected subcutaneously with physiological saline at the same time and frequency as those in the drug administration group. On the 15th day, a video recorder was used to observe and record the itch behavioral changes of the mice.
  • mice The severity of itch between groups was observed through the behavioral scratching count of mice.
  • Compound A the mice were placed in a transparent observation cage and filmed for 90 minutes in a quiet environment without people. The video was played back to record the behavioral tickling number of the mice.
  • a tickling event is when the mouse raises its hind paws to scratch the shaved area once or multiple times in a row. The tickling event ends when the mouse's hind paws fall to the ground or retract its paws and pause.
  • a rat variant asthma model was first constructed, and then Compound A was used to treat the mice and its efficacy was observed.
  • Animals SD rats 6-8 weeks old, male 200-250g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008.
  • Animal breeding environment temperature (24+2)°C, relative humidity 50% to 70%, and 12h: 12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
  • A02AI ultrasonic nebulizer Shanghai Yuyue Medical Equipment Co., Ltd.
  • the rats were randomly divided into three groups (blank group, model control group, and compound A group), with 6 rats in each group.
  • On the first day 2 mg of ovalbumin (OVA) and 100 mg AI(OH) 3 were intraperitoneally injected. After 3 weeks, 0.01 mg OVA and 100 mg AI(OH) 3 were intraperitoneally injected again.
  • the blank group was injected with normal saline.
  • the model control group and Compound A group began to use 1% OVA for aerosol challenge, and the normal control group used physiological saline once every other day for a total of 7 times.
  • Administration began on the day of atomization.
  • Compound A (0.6 mg/kg) was administered to the administration group 30 minutes before atomization.
  • the model control group and the normal control group were administered the same amount of drinking water once a day, a total of 14 times.
  • the rats in each group were placed in the atomization box and inhaled atomized 10-4 mol/L capsaicin solution for 60 seconds, and the number of coughs of each rat within 2 minutes was recorded.
  • the compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.

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Abstract

La présente invention concerne le domaine technique de la biomédecine. Il a été découvert, selon la présente invention, qu'un composé représenté dans la formule I, ou un isomère optique ou un racémate de celui-ci, ou un solvate de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci peut être utilisé pour préparer un médicament ou une préparation, et le médicament ou la préparation est utilisée pour : (a) l'inhibition de l'activité d'un canal TRPA1 ; et (b) le traitement de maladies associées au canal TRPA1. Il a été démontré dans des expériences que le composé représenté par la formule (I) a un bon effet inhibiteur sur le canal TRPA1, et le composé représenté par la formule (I) de la présente invention peut être utilisé pour le traitement de la douleur, de l'inflammation, de troubles respiratoires (tels que des troubles de la respiration), du prurit, de troubles cutanés (acné, boutons), de troubles du tractus urinaire, d'une maladie intestinale inflammatoire, etc.
PCT/CN2022/138608 2022-04-22 2022-12-13 Utilisation d'un composé sesquiterpénoïde dans l'inhibition de l'activité du canal trpa1 WO2023202102A1 (fr)

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