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CN-121987614-A - GPR35 receptor agonist or medicine and application thereof

CN121987614ACN 121987614 ACN121987614 ACN 121987614ACN-121987614-A

Abstract

The invention relates to the technical field of medicines, and discovers that a natural product amentoflavone can be used as a GPR35 (G-protein coupled receptor, GPR 35) receptor agonist and application thereof, wherein the compound is amentoflavone (Amentoflavone), has GPR35 receptor agonistic activity, is a GPR35 receptor agonist, can treat thromboembolic diseases, vernal conjunctivitis, intracranial embolism, primary sclerosing cholangitis and myocardial infarction, and can provide a GPR35 receptor agonist seedling compound with definite action targets and novel action targets for the related diseases.

Inventors

  • LIU YANFANG
  • HOU TAO
  • XU FANGFANG
  • WANG JIXIA
  • XU QING
  • SONG JIA

Assignees

  • 赣江中药创新中心

Dates

Publication Date
20260508
Application Date
20241108

Claims (8)

  1. 1. The application of the amentoflavone compound as a GPR35 receptor agonist or in preparing medicaments is characterized in that the GPR35 receptor agonist or the prepared medicaments contain the amentoflavone compound or derivatives of the amentoflavone compound, and one or more than two of the amentoflavone compounds corresponding to pharmaceutically acceptable salt forming components are active ingredients.
  2. 2. The method of claim 1, wherein the amentoflavone compound has the formula:
  3. 3. The use according to claim 1, wherein the prepared medicament is one or more than two medicaments for treating and/or preventing diseases such as thromboembolic diseases, vernal conjunctivitis, intracranial embolism, primary sclerosing cholangitis and myocardial infarction.
  4. 4. The method according to claim 1 to 3, wherein the GPR35 receptor agonist or the medicament further comprises a pharmaceutically acceptable carrier and/or excipient.
  5. 5. A medicine or GPR35 receptor agonist is characterized in that amentoflavone compound or derivatives of amentoflavone compound and one or more than two of amentoflavone compounds corresponding to pharmaceutically acceptable salts are used as active ingredients.
  6. 6. The drug or GPR35 receptor agonist according to claim 5, wherein: Amentoflavone has the following chemical structure:
  7. 7. The pharmaceutical composition of claim 5 or 6, wherein the pharmaceutical composition or GPR35 receptor agonist further comprises a pharmaceutically acceptable carrier and/or excipient.
  8. 8. The drug or GPR35 receptor agonist according to claim 5 or 6, wherein the drug is a drug for the treatment and/or prevention of one or more of thromboembolic diseases, vernal conjunctivitis, intracranial embolism, primary sclerosing cholangitis and myocardial infarction.

Description

GPR35 receptor agonist or medicine and application thereof Technical Field The invention belongs to the field of GPR35 (G-protein coupled receptor, GPR 35) receptor agonists, relates to the discovery of a biflavone compound action target point in ginkgo biloba, and particularly relates to the discovery of a amentoflavone action target point in biflavone compounds. The biflavone compound amentoflavone, the derivatives and the corresponding pharmaceutically acceptable salt-forming compounds thereof are GPR35 receptor, and the application is thromboembolic diseases, vernal conjunctivitis, intracranial embolism, primary sclerosing cholangitis and myocardial infarction. Background Ginkgo biloba is a plant of Ginkgo genus of Ginkgoaceae, also known as semen Ginkgo, gongsun tree, fructus Bruceae, duck foot tree, and fant, and is one of the oldest and rare species of the wig in the middle-aged, and called "activated stone". The ginkgo has complex chemical components, the most main active substances are flavonoids and terpene lactone compounds, wherein the flavonoids can be divided into monoflavone, biflavone and the like, and the biflavone is a characteristic component of gymnosperm and is widely distributed in ginkgo plants. The ginkgolide She Shuanghuang is a dimer formed by connecting two molecules of monoflavone, and has higher biological activity compared with a monomer and good application prospect. Clinical key pharmacological studies show that ginkgo biflavanoid has the functions of resisting inflammation, resisting oxidation, resisting microorganism, resisting cancer, protecting nerves, preventing and treating cardiovascular diseases, lowering blood sugar and the like (Zhang Zhongpeng, liu Xiufen. Summary of the development of ginkgo leaf extract, chinese medicine research and information, 2005,7 (2): 38-40; tu Qingbo, sun Yun, xu Ting and the like. Research progress of pharmacological actions of ginkgo biflavanoid. Shandong medicine ,2018,58(19):112-114;JIA X,CHEN J,LIN H,et al.Disposition of flavonoids via enteric recycling:enzyme-transporter coupling affects metabolism of biochanin A and formononetin and excretion of their phase II conjugates.J Pharmacol Exp Ther,2004,310(3):1103-1113; Zhang Zun tin, gao Runli, zhuang Sukai. Synthesis of biflavanoid and actions with DNA. Pharmaceutical science report ,2009,44(8):873-878;SAGRERA G,BERTUCCI A,VAZQUEZ A,et al.Synthesis and antifungal activities of natural and synthetic biflavonoids.Bioorg Med Chem,2011,19(10):3060-3073;JOYEUX M,LOBSTEINA,ANTON R,et al.Comparative antilipoperoxidant,antinecrotic and scavenging properties of terpenes and biflavones from Ginkgo and some flavonoids.PlantaMed,1995,61(2):126-129;QIAO Y,LIU X,LI X,et al.Biflavonoids from Juniperus oblonga inhibit organic anion transporter 3.Biochem Biophys Res Commun,2019,509(4):931-936). GPR35 receptor is an orphan receptor containing 309 amino acids belonging to the superfamily of G protein-coupled receptors. GPR35 receptor is expressed in various tissues including immune cells, colon, pancreas, small intestine and spleen, wherein the expression level is higher in human colon cancer cells HT-29 cells. Current studies indicate that GPR35 receptor is associated with diseases such as asthma, heart failure, hypertension, ulcerative colitis, primary sclerosing cholangitis, coronary heart disease, metabolic syndrome, pain and cancer. The discovery and validation of new ligands for the GPR35 receptor is of great significance for elucidating its pharmacological and biological functions, which will provide a new direction for targeted treatment of diseases (O'DowdB F,Nguyen T,Marchese A,Cheng R,Lynch K R,Heng H H Q,Kolakowski L F,George SR.Genomics 47(1998)310-313;Taniguchi Y,Tonai-Kachi H,Shijo K.FEBS Lett 580(2006)5003-5008;Wang J,Simonavicius N,Wu X,Swaminath G,Reagan J,Tian H,Ling L.J Biol Chem 281(2006)22021-22028;YYang,J Y LLu,X Wu,S Summer,J Whoriskey,C Saris,J D Reagan.Pharmacology86(2010)1-5;H Deng,Y Fang.Pharmacology 89(2012)211-219;Huayun Deng,Ye Fang.Med Chem Commun 3(2012)1270-1274;Abdalhameed MM,Zhao PW,Hurst DP,Reggio PH,Abood ME,Croatt MP,Bioorganic&Medicinal Chemistry Letters 27(2017)612-615). At present, research on the amentoflavone of biflavanoid compounds on diseases such as thromboembolic diseases, vernal conjunctivitis, intracranial embolism, primary sclerosing cholangitis, myocardial infarction and the like by GPR35 receptor (G-protein coupled receptor, GPR 35) has not been reported. Disclosure of Invention The invention relates to the discovery of an action target point of amentoflavone in biflavanoid compounds and application of the compounds, one of the purposes is to provide the action target point of amentoflavone as a GPR35 receptor, and the other purpose is to provide the application range of the compounds in clinic. The technical scheme of the invention is as follows: The GPR35 receptor agonist is Compound spica fir biflavones. The chemical structure of the compound ament