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Conflitti_2022_frontpharm
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
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  • 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)
Liver inflammation
REV5901 derivatives
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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Language
  • English
Classification
Medicine
License
CC BY
Open access status
gold
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Persistent URL
https://n2t.net/ark:/12658/srd1328321
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