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

  • Bioorg Med Chem. 2011 May 15;19(10):3039-53. doi: 10.1016/j.bmc.2011.04.014.
Christoffer Bengtsson  1 ,  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
Affiliations
  • 1. AstraZeneca Research and Development, Mölndal, Sweden.
PMID: 21515056 DOI: 10.1016/j.bmc.2011.04.014
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.

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