Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)

被引：197

作者：

Tully, David C. ^{[1
,2
]}

Rucker, Paul V. ^{[1
]}

Chianelli, Donatella ^{[1
]}

Williams, Jennifer ^{[1
]}

Vidal, Agnes ^{[1
]}

Alper, Phil B. ^{[1
]}

Mutnick, Daniel ^{[1
]}

Bursulaya, Badry ^{[1
]}

Schmeits, James ^{[1
]}

Wu, Xiangdong ^{[1
]}

Bao, Dingjiu ^{[1
]}

Zoll, Jocelyn ^{[1
]}

Kim, Young ^{[1
]}

Groessl, Todd ^{[1
]}

McNamara, Peter ^{[1
]}

Seidel, H. Martin ^{[1
,4
]}

Molteni, Valentina ^{[1
]}

Liu, Bo ^{[1
]}

Phimister, Andrew ^{[2
,3
]}

Joseph, Sean B. ^{[1
,5
]}

Laffitte, Bryan ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[2] Novartis Inst Biomed Res, Emeryville, CA 94608 USA

[3] STA Pharmaceut, San Diego, CA 92121 USA

[4] IFM Therapeut, Boston, MA 02116 USA

[5] Calibr, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 24期

关键词：

FAMILIAL INTRAHEPATIC CHOLESTASIS; PRIMARY BILIARY CHOLANGITIS; OBETICHOLIC ACID; RECEPTOR FXR; METABOLISM; SERIES; ITCH;

D O I：

10.1021/acs.jmedchem.7b00907

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9960 / 9973

页数：14

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