- Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.
Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.
Bioorganic & medicinal chemistry (2011-04-26)
Christoffer Bengtsson, Stefan Blaho, David Blomberg Saitton, Kay Brickmann, Johan Broddefalk, Ojvind Davidsson, Tomas Drmota, Rutger Folmer, Kenth Hallberg, Stefan Hallén, Ragnar Hovland, Emre Isin, Petra Johannesson, Bengt Kull, Lars-Olof Larsson, Lars Löfgren, Kristina E Nilsson, Tobias Noeske, Nick Oakes, Alleyn T Plowright, Volker Schnecke, Pernilla Ståhlberg, Pernilla Sörme, Hong Wan, Eric Wellner, Linda Oster
PMID21515056
ABSTRACT
Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.
MATERIALS