Exploration of Novel Urolithin C Derivatives asNon-Competitive Inhibitors of Liver Pyruvate Kinase

Abstract:

The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholicfatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually tocirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allostericinhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure–activity analysisof urolithin C was carried out. More than 50 analogues were synthesized and tested regardingthe chemical features responsible for the desired activity. These data could pave the way to thedevelopment of more potent and selective PKL allosteric inhibitors.

Keywords: NAFLD; liver pyruvate kinase; allosteric inhibitors; urolithin C; SAR studies