Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase
Umberto Maria Battisti, Leticia Monjas, Fady Akladios, Josipa Matić, E.G. Andresen, Carolin H. Nagel, Malin Hagkvist, Liliana Håversen, Woonghee Kim, Mathias Uhlén, Jan Borén, Adil Mardinoğlu, Morten Grøtli
Abstract
The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure-activity analysis of urolithin C was carried out. More than 50 analogues were synthesized and tested regarding the chemical features responsible for the desired activity. These data could pave the way to the development of more potent and selective PKL allosteric inhibitors.