Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease
Informazioni aggiuntive
Autori
Fiorucci S.,
Rapacciuolo P.,
Fiorillo B.,
Roselli R.,
Marchianò S.,
Di Giorgio C.,
Bordoni M.,
Bellini R.,
Cassiano C.,
Conflitti P.,
Catalanotti B.,
Limongelli V.,
Sepe V.,
Biagioli M.,
Zampella A.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2022
Lingua
Inglese
Sommario
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.
Parole chiave
Cysteinyl-leukotriene-receptor 1, G-protein coupled bile acid receptor 1, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis (NASH), Liver inflammation, REV5901 derivatives
Periodico
Frontiers in pharmacology
Volume
13
Pagine (o numero dell’articolo)
858137
Diffusione
Licenza
CC BY
Visibilità
Pubblico
Status open access
Gold
