AUTHOR=Finamore Claudia , De Marino Simona , Cassiano Chiara , Napolitano Giuliano , Rapacciuolo Pasquale , Marchianò Silvia , Biagioli Michele , Roselli Rosalinda , Di Giorgio Cristina , Festa Carmen , Fiorucci Stefano , Zampella Angela 

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

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 12 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1425867

DOI=10.3389/fchem.2024.1425867

ISSN=2296-2646

ABSTRACT=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, a bile acid analogue. BAR502 is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. 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 LC-MS 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.