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

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

  • J Med Chem. 2017 Dec 28;60(24):9960-9973. doi: 10.1021/acs.jmedchem.7b00907.
David C Tully 1 2,  Paul V Rucker 1,  Donatella Chianelli 1,  Jennifer Williams 1,  Agnès Vidal 1,  Phil B Alper 1,  Daniel Mutnick 1,  Badry Bursulaya 1,  James Schmeits 1,  Xiangdong Wu 1,  Dingjiu Bao 1,  Jocelyn Zoll 1,  Young Kim 1,  Todd Groessl 1,  Peter McNamara 1,  H Martin Seidel 1,  Valentina Molteni 1,  Bo Liu 1,  Andrew Phimister 2,  Sean B Joseph 1,  Bryan Laffitte 1
Affiliations

Affiliations

  • 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.
PMID: 29148806 DOI: 10.1021/acs.jmedchem.7b00907
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.

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