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

Front Chem. 2024 Jul 17:12:1425867. doi: 10.3389/fchem.2024.1425867. eCollection 2024.

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.

Keywords: BAR502; anti-inflammatory activity; bile acid receptors; cell permeation; fibrates; hybrid prodrug; metabolic profile; stability.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by a grant from the Italian MIUR/PRIN 2022 (20223K7L88). This study was partially supported by a research grant from BARPharmaceuticals SrL, Italy. MS data were provided by the Analisi Strumentale laboratory of the Department of Pharmacy, University of Naples Federico II. The authors declare that this study received funding from BARPharmaceuticals SrL. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.