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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

2011; Elsevier BV; Volume: 19; Issue: 10 Linguagem: Inglês

10.1016/j.bmc.2011.04.014

1464-3391

Christoffer Bengtsson, Stefan Blaho, David Blomberg Saitton, Kay Brickmann, Johan Broddefalk, Öjvind Davidsson, Tomáš Drmota, R.H.A. Folmer, Kenth Hallberg, Stefan Hallén, Ragnar Hovland, Emre M. Isin, Petra Johannesson, Bengt Kull, Lars-Olof Larsson, Lars Löfgren, Kristina Nilsson, Tobias Noeske, Nick Oakes, Alleyn T. Plowright, Volker Schnecke, Pernilla Ståhlberg, Pernilla Sörme, Hong Wan, Eric Wellner, Linda Öster,

Peroxisome Proliferator-Activated Receptors

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.