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
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.
Funder
Ministero dell’Istruzione, dell’Università e della Ricerca
European Research Council
Centro Svizzero di Calcolo Scientifico
Subject
Pharmacology (medical),Pharmacology
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