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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.858137

DOI=10.3389/fphar.2022.858137

ISSN=1663-9812

ABSTRACT=<p>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 (CysLT<sub>1</sub>R) 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 CystLT<sub>1</sub>R 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 CysLT<sub>1</sub>R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development.</p>