RGD Reference Report - Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). - Rat Genome Database

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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).

Authors: Tully, David C  Rucker, Paul V  Chianelli, Donatella  Williams, Jennifer  Vidal, Agn├Ęs  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 
Citation: Tully DC, etal., J Med Chem. 2017 Dec 28;60(24):9960-9973. doi: 10.1021/acs.jmedchem.7b00907. Epub 2017 Dec 8.
RGD ID: 15042869
Pubmed: (View Article at PubMed) PMID:29148806
DOI: Full-text: DOI:10.1021/acs.jmedchem.7b00907

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.



Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)


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