- Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio
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The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non-steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.
- Gu, Yipei,Leng, Ying,Ning, Mengmeng,Shen, Jianhua,Tang, Xuehang,Yan, Hongyi,Ye, Yangliang
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- FARNESOID X RECEPTOR MODULATING COMPOUNDS AND METHODS OF USING THE SAME
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Provided are compounds that can act as a modulator of a farnesoid X receptor (FXR) and that can be useful in the treatment of diseases and/or disorders associated with the FXR. Compositions including such compounds are also provided along with methods for preparing compounds of the present invention and their use.
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Paragraph 0166-0167
(2021/08/20)
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- Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator
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Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.
- Luo, Guoshun,Lin, Xin,Li, Zhenbang,Xiao, Maoxu,Li, Xinyu,Zhang, Dayong,Xiang, Hua
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- Isoxazole FXR receptor agonist as well as preparation method and medical application thereof
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The invention belongs to the field of medicinal chemistry, and particularly relates to an isoxazole FXR receptor agonist and a preparation method and medical application thereof. The invention relates to a compound as shown in a formula (I), and pharmaceutically acceptable salts and isotope markers thereof. The compound as shown in the formula (I), the pharmaceutically acceptable salts and the isotope markers thereof have FXR receptor agonist activity and can be applied to preparation of drugs for treating or preventing hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis and type II diabetes mellitus.
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Paragraph 0048-0050
(2021/07/14)
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- COMPOSITIONS AND METHODS FOR TREATING LIVER DISORDERS
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The present disclosure is directed to FXR agonists, pharmaceutical compositions thereof, and methods of using the same for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, either alone or in combination with thyroid receptor agonists.
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- 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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Paragraph 0092; 0095; 0098; 0143; 0145-0147; 0149
(2021/05/22)
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- FXR RECEPTOR AGONIST
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The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer of the compound, the salt or the ester, wherein
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Paragraph 0272; 0287-0288
(2020/06/02)
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- COMPOUNDS USEFUL IN MODULATING THE FARNESOID X RECEPTOR AND METHODS OF MAKING AND USING THE SAME
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Provided are compounds that can act as a modulator of a farnesoid X receptor (FXR) and that can be useful in the treatment of diseases and/or disorders associated with the FXR. Compositions including such compounds are also provided along with methods for preparing compounds of the present invention and their use.
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Page/Page column 32; 34
(2020/03/02)
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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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- COMBINATIONS COMPRISING BENZODIOXOL AS GLP-1R AGONISTS FOR USE IN THE TREATMENT OF NASH/NAFLD AND RELATED DISEASES
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In part, the invention provides a new combination comprising (1) a GLP-1R agonist and (2) an ACC inhibitor or a DGAT2 inhibitor, or a KHK inhibitor or FXR agonist. The invention further provides new methods for treating diseases and disorders, for example, fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes, for example, using the new combination described herein.
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Page/Page column 364; 366
(2020/12/07)
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- AN ISOXAZOLE DERIVATIVES AS NUCLEAR RECEPTOR AGONISTS AND USED THEREOF
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The present invention relates to isoxazole derivatives, including pharmaceutical compositions and for the preparation of isoxazole derivatives. And more particularly the present invention provided a pharmaceutical composition of isoxazole derivatives for activation of Farnesoid X receptor(FXR, NR1H4).
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Paragraph 601-604; 1817-1819
(2018/11/10)
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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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supporting information
p. 9960 - 9973
(2018/01/11)
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- COMPOSITIONS AND METHODS FOR MODULATING FXR
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The present invention relates to compounds of Formula (I), a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesiod X receptors (FXR).
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Page/Page column 80; 82
(2012/07/13)
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- COMPOSITIONS AND METHODS FOR MODULATING FARNESOID X RECEPTORS
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The present invention relates to compounds of Formula I, a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesiod X receptors (FXR).
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Page/Page column 39; 41
(2012/07/13)
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- COMPOSITIONS AND METHODS FOR MODULATING FARNESOID X RECEPTORS
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The present invention relates to compounds of Formula (I), a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful
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Page/Page column 39; 40 ; 41
(2012/07/13)
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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 25
(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 36
(2008/06/13)
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