Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease
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Fiorucci, Stefano
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Rapacciuolo, Pasquale
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Fiorillo, Bianca
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Roselli, Rosalinda
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Marchianò, Silvia
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Di Giorgio, Cristina
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Bordoni, Martina
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Bellini, Rachele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Cassiano, Chiara
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Conflitti, Paolo
ORCID
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Catalanotti, Bruno
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Limongelli, Vittorio
ORCID
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy ; Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Sepe, Valentina
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Biagioli, Michele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Zampella, Angela
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Published in:
- Frontiers in pharmacology. - 2022, vol. 13, p. 858137
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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Medicine
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CC BY
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gold
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https://n2t.net/ark:/12658/srd1328321
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