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

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.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non–Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers

“…Tropifexor is likely a Biopharmaceutics Classification System Class II compound due to its low solubility and high permeability . As anticipated, when tropifexor was taken with a high‐fat meal, there was an increase of ∼60% in the systemic exposure of tropifexor and its metabolite CKS577.…”

“…Consistent with the observed t 1/2 (range, 13.5‐21.9 hours), steady‐state tropifexor levels were reached by day 4 with <2‐fold accumulation following a once‐daily dosing regimen. Moderate‐to‐slow absorption (median t max of ∼4 hours) was observed following single or multiple oral dosing, possibly due to the low aqueous solubility of tropifexor . Overall, tropifexor demonstrated pharmacokinetic properties that would support a once‐daily dosing regimen in future clinical trials.…”

“…Tropifexor is a highly potent, orally available, non–bile acid FXR agonist that has shown effective target engagement in cell‐based assays and in vivo experiments in rodents . Its potency has been attributed to the inclusion of a bicyclic nortropine‐substituted benzothiazole carboxylic acid .…”

“…Tropifexor is a highly potent, orally available, non–bile acid FXR agonist that has shown effective target engagement in cell‐based assays and in vivo experiments in rodents . Its potency has been attributed to the inclusion of a bicyclic nortropine‐substituted benzothiazole carboxylic acid . Recently, preclinical validation of tropifexor was performed in various animal models of cholestasis and NASH, demonstrating effective reduction in various disease parameters including fibrosis .…”

Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

“…FXR activation proved effective at decreasing hepatic steatosis and fibrosis, revealed anti‐diabetic activity and has anti‐inflammatory properties . Currently, several FXR agonists such as the steroid obeticholic acid ( 2 ) and derivatives of the widely used reference compound GW4064 ( 3 ) are studied in clinical trials for the treatment of NASH. However, full FXR agonists may cause marked adverse effects by repressing cholesterol 7α‐hydroxylase (CYP7A1) which leads to loss of metabolic cholesterol elimination .…”