2. Academic Validation
  3. 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

  • 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

Affiliation

  • 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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