<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
  <dc:creator>Fiorucci, Stefano</dc:creator>
  <dc:creator>Rapacciuolo, Pasquale</dc:creator>
  <dc:creator>Fiorillo, Bianca</dc:creator>
  <dc:creator>Roselli, Rosalinda</dc:creator>
  <dc:creator>Marchianò, Silvia</dc:creator>
  <dc:creator>Di Giorgio, Cristina</dc:creator>
  <dc:creator>Bordoni, Martina</dc:creator>
  <dc:creator>Bellini, Rachele</dc:creator>
  <dc:creator>Cassiano, Chiara</dc:creator>
  <dc:creator>Conflitti, Paolo</dc:creator>
  <dc:creator>Catalanotti, Bruno</dc:creator>
  <dc:creator>Limongelli, Vittorio</dc:creator>
  <dc:creator>Sepe, Valentina</dc:creator>
  <dc:creator>Biagioli, Michele</dc:creator>
  <dc:creator>Zampella, Angela</dc:creator>
  <dc:date>2022</dc:date>
  <dc:description xmlns:ns0="xml" ns0:lang="en">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.</dc:description>
  <dc:format>application/pdf</dc:format>
  <dc:identifier>https://localhost:5000/ark:/12658/srd1328321</dc:identifier>
  <dc:identifier>https://susi.usi.ch/global/documents/328321</dc:identifier>
  <dc:identifier>https://susi.usi.ch/documents/328321/files/Conflitti_2022_frontpharm.pdf</dc:identifier>
  <dc:language>eng</dc:language>
  <dc:relation>info:eu-repo/semantics/altIdentifier/doi/10.3389/fphar.2022.858137</dc:relation>
  <dc:relation>info:eu-repo/semantics/altIdentifier/ark/12658/srd1328321</dc:relation>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>CC BY</dc:rights>
  <dc:source>Frontiers in pharmacology. - 2022, vol. 13, p. 858137</dc:source>
  <dc:subject xmlns:ns1="xml" ns1:lang="en">Cysteinyl-leukotriene-receptor 1</dc:subject>
  <dc:subject xmlns:ns2="xml" ns2:lang="en">G-protein coupled bile acid receptor 1</dc:subject>
  <dc:subject xmlns:ns3="xml" ns3:lang="en">Nonalcoholic fatty liver disease</dc:subject>
  <dc:subject xmlns:ns4="xml" ns4:lang="en">Nonalcoholic steatohepatitis (NASH)</dc:subject>
  <dc:subject xmlns:ns5="xml" ns5:lang="en">Liver inflammation</dc:subject>
  <dc:subject xmlns:ns6="xml" ns6:lang="en">REV5901 derivatives</dc:subject>
  <dc:subject>info:eu-repo/classification/udc/61</dc:subject>
  <dc:title xmlns:ns7="xml" ns7:lang="en">Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease</dc:title>
  <dc:type>http://purl.org/coar/resource_type/c_6501</dc:type>
</oai_dc:dc>