Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease

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

doi:10.3389/fphar.2022.858137

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Journal article

Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease

Fiorucci, Stefano Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Rapacciuolo, Pasquale Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Fiorillo, Bianca Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Roselli, Rosalinda Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Marchianò, Silvia Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Di Giorgio, Cristina Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Bordoni, Martina Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Bellini, Rachele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Cassiano, Chiara Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Conflitti, Paolo ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Catalanotti, Bruno Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Limongelli, Vittorio ORCID Department of Pharmacy, University of Naples “Federico II”, Naples, Italy ; Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Sepe, Valentina Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Biagioli, Michele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Zampella, Angela Department of Pharmacy, University of Naples “Federico II”, Naples, Italy

2022

Published in:

Frontiers in pharmacology. - 2022, vol. 13, p. 858137

Cysteinyl-leukotriene-receptor 1

G-protein coupled bile acid receptor 1

Nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH)

English 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.

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