- PPARs-FXR multi-target micromolecular agonist as well as preparation method and application thereof
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The invention discloses a PPARs-FXR multi-target micromolecule agonist and a preparation method and application thereof, the structure is shown in a general formula I, and the definition of each substituent group is shown in the description and claims. Th
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- Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis
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Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.
- Azzara, Anthony V.,Cao, Gary G.,Carpenter, Joseph,Cook, Erica M.,Ellsworth, Bruce Alan,Krupinski, Jack,Mosure, Kathy,Rossi, Karen A.,Sitkoff, Doree,Soars, Matthew G.,Wacker, Dean A.,Wang, Tao,Wang, Ying,Wu, Gang,Zhuo, Xiaoliang,Ziegler, Milinda
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p. 1413 - 1420
(2021/08/31)
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- Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen-induced hepatotoxicity
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Acetaminophen (APAP) overdose is a leading cause of acute hepatic failure and liver transplantation, while the existing treatments are poorly effective. Therefore, it is necessary to develop effective therapeutic drugs for APAP-induced hepatotoxicity. Farnesoid X receptor (FXR) is a potential target for the treatment of liver disease, and the activation of FXR protects mice against APAP-induced hepatotoxicity. Compound 5, a glycine-conjugated derivative of FXR agonist 4, was designed to extend the chemical space of existing FXR agonists. Molecular modeling study indicated that compound 5 formed hydrogen bond network with key residues of FXR. Moreover, compound 5 (10?mg/kg) revealed better protective effects against APAP-induced hepatotoxicity than parent compound 4 (30?mg/kg). Further mechanical research indicated that compound 5 regulated the expressions of genes related to FXR and oxidative stress. These findings suggest that compound 5 is a promising FXR agonist suitable for further research, and it is the first time to verify that the glycine-conjugated derivative five exerted better protective effects than its parent compound.
- Cai, Zongyu,Deng, Liming,Hu, Lijun,Li, Zheng,Ren, Qiang,Wang, Bin,Wang, Guangji,Zhao, Xin,Zhou, Zongtao
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- COMPOUNDS FOR MODULATING FXR
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Provided herein are compounds of Formula (I), a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).
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- Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
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Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
- Li, Junyou,Liu, Mengqi,Li, Yazhou,Sun, Dan-Dan,Shu, Zhihao,Tan, Qian,Guo, Shimeng,Xie, Rongrong,Gao, Lixin,Ru, Hongbo,Zang, Yi,Liu, Hong,Li, Jia,Zhou, Yu
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p. 12748 - 12772
(2020/12/17)
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- MULTICYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- ALKENE COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I): Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- SPIROCYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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- Fluorine-containing isoxazole compound as well as preparation method, pharmaceutical composition and application thereof (by machine translation)
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The invention relates to a fluorine-containing isoxazole compound and a preparation method, a pharmaceutical composition and application thereof. In particular, the present invention discloses a I compound represented by formula (I) or an enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof. And discloses that the compound is a small FXR molecule agonist targeting a molecule, and can be used for treating FXR the disease mediated by the disease. (by machine translation)
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- A spiro compound, its preparation method, composition and use thereof
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The invention discloses a spiro compound, preparation method thereof, and use of the composition. The spiro compounds have the following formula (I) structure. The invention spiro compounds can be effective therapy [...] X receptor-mediated disease, more stable, long half-life.
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- Spiro compound and medicinal use thereof
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The invention relates to a spiro compound serving as a FXR receptor agonist, whose chemical structure is shown in type I, pharmaceutically acceptable salts of the spiro compound, or the enantiomers, diastereomers, tautomers, racemates, solvates, N-oxide or amino acid conjugates and the pharmaceutical compositions of the spiro compound, and the use in preparing drugs for treatment of diseases mediated by the FXR receptor.
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- Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)
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The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.
- Tully, David C.,Rucker, Paul V.,Chianelli, Donatella,Williams, Jennifer,Vidal, Agnès,Alper, Phil B.,Mutnick, Daniel,Bursulaya, Badry,Schmeits, James,Wu, Xiangdong,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Groessl, Todd,McNamara, Peter,Seidel, H. Martin,Molteni, Valentina,Liu, Bo,Phimister, Andrew,Joseph, Sean B.,Laffitte, Bryan
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p. 9960 - 9973
(2018/01/11)
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- Heterocyclic farnesoid X receptor modifier
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The invention relates to a preparation method of a heterocyclic compound and a composition with components the same as those of the heterocyclic compound and application of the heterocyclic compound as a farnesoid X receptor active modifier. The modifier is the heterocyclic compound shown as the formula I or salt acceptable pharmaceutically or a predrug or a solvent compound or a polycrystal or an isomer or a stable isotope derivative. The compound can be used for treating or preventing related diseases mediated by FXR, and the related diseases are caused by saccharide or lipid or bile metabolic disturbance. The formula I is shown in the specification.
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Paragraph 0128; 0132
(2017/07/21)
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- Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
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The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
- Genin, Michael J.,Bueno, Ana B.,Agejas Francisco, Javier,Manninen, Peter R.,Bocchinfuso, Wayne P.,Montrose-Rafizadeh, Chahrzad,Cannady, Ellen A.,Jones, Timothy M.,Stille, John R.,Raddad, Eyas,Reidy, Charles,Cox, Amy,Michael, M. Dodson,Michael, Laura F.
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p. 9768 - 9772
(2016/01/12)
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula (I): formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and diseases related to dyslipidemia.
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Page/Page column 21
(2009/03/07)
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula. wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
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Page/Page column 11
(2008/06/13)
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