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Abstract Details
Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)
Tully DC1,2, Rucker PV1, Chianelli D1, Williams J1, Vidal A1, Alper PB1, Mutnick D1, Bursulaya B1, Schmeits J1, Wu X1, Bao D1, Zoll J1, Kim Y1, Groessl T1, McNamara P1, Seidel HM1, Molteni V1, Liu B1, Phimister A2, Joseph SB1, Laffitte B1. J Med Chem. 2017 Dec 28;60(24):9960-9973. doi: 10.1021/acs.jmedchem.7b00907. Epub 2017 Dec 8.
Author information
1
Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
2
Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
Abstract
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.