Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

Stefano Fiorucci; Pasquale Rapacciuolo; Bianca Fiorillo; Rosalinda Roselli; Silvia Marchianò; Cristina Di Giorgio; Martina Bordoni; Rachele Bellini; Chiara Cassiano; Paolo Conflitti; Bruno Catalanotti; Vittorio Limongelli; Valentina Sepe; Michele Biagioli; Angela Zampella

doi:10.3389/fphar.2022.858137

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT₁R Modulator for the Treatment of Metabolic Fatty Liver Disease

Front Pharmacol. 2022 Apr 25:13:858137. doi: 10.3389/fphar.2022.858137. eCollection 2022.

Authors

Stefano Fiorucci¹, Pasquale Rapacciuolo², Bianca Fiorillo², Rosalinda Roselli², Silvia Marchianò¹, Cristina Di Giorgio¹, Martina Bordoni¹, Rachele Bellini¹, Chiara Cassiano², Paolo Conflitti³, Bruno Catalanotti², Vittorio Limongelli^{2

3}, Valentina Sepe², Michele Biagioli¹, Angela Zampella²

Affiliations

¹ Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
² Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
³ Faculty of Biomedical Sciences, Euler Institute, Università della Svizzera italiana (USI), Lugano, Switzerland.

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two highly prevalent human diseases caused by excessive fat deposition in the liver. Although multiple approaches have been suggested, NAFLD/NASH remains an unmet clinical need. Here, we report the discovery of a novel class of hybrid molecules designed to function as cysteinyl leukotriene receptor 1 (CysLT₁R) antagonists and G protein bile acid receptor 1 (GPBAR1/TGR5) agonists for the treatment of NAFLD/NASH. The most potent of these compounds generated by harnessing the scaffold of the previously described CystLT₁R antagonists showed efficacy in reversing liver histopathology features in a preclinical model of NASH, reshaping the liver transcriptome and the lipid and energy metabolism in the liver and adipose tissues. In summary, the present study described a novel orally active dual CysLT₁R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development.

Keywords: REV5901 derivatives; cysteinyl-leukotriene-receptor 1; g-protein coupled bile acid receptor 1; liver inflammation; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis (NASH).