gw-4064 and Cholestasis

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.

Topics: Administration, Oral; Animals; Benzothiazoles; Biological Availability; Cholestasis; Dogs; Drug Evaluation, Preclinical; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Isoxazoles; Male; Microsomes, Liver; Non-alcoholic Fatty Liver Disease; Piperidines; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship; Triglycerides

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

Topics: Administration, Oral; Animals; Carboxylic Acids; Cholestasis; Crystallography, X-Ray; Disease Models, Animal; DNA-Binding Proteins; Dogs; Gastric Mucosa; Haplorhini; Isoxazoles; Mice; Molecular Conformation; Molecular Structure; Naphthalenes; Rats; Receptors, Cytoplasmic and Nuclear; Stomach; Structure-Activity Relationship; Transcription Factors

A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

Topics: Animals; Anticholesteremic Agents; Cell Line; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Humans; Ligands; Liver; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship; Transcription Factors