BAR502/fibrate conjugates: synthesis, biological evaluation and metabolic profile

TL;DR

Scientists combined a bile acid analog with fibrates to create new compounds that may help treat cholestasis and NASH by activating specific receptors.

Contribution

The paper introduces a novel library of BAR502-fibrate conjugates with promising pharmacological properties.

Findings

Compound 1 showed the highest activity among the conjugates tested.

Compound 1 is hydrolyzed in mice to release clofibric acid and BAR505, which retain dual FXR/GPBAR1 activity.

Compound 1 demonstrated good stability and cell permeation.

Abstract

BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.

Figures