Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

  • Bioorg Med Chem Lett. 2010 Apr 1;20(7):2383-8. doi: 10.1016/j.bmcl.2009.04.091.
Jeffrey W Corbett  1 ,  Kevin D Freeman-Cook ,  Richard Elliott ,  Felix Vajdos ,  Francis Rajamohan ,  Darcy Kohls ,  Eric Marr ,  Hailong Zhang ,  Liang Tong ,  Meihua Tu ,  Sharad Murdande ,  Shawn D Doran ,  Janet A Houser ,  Wei Song ,  Christopher J Jones ,  Steven B Coffey ,  Leanne Buzon ,  Martha L Minich ,  Kenneth J Dirico ,  Susan Tapley ,  R Kirk McPherson ,  Eliot Sugarman ,  H James Harwood Jr ,  William Esler
Affiliations
  • 1. Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. [email protected]
PMID: 20219367 DOI: 10.1016/j.bmcl.2009.04.091
Abstract

Screening Pfizer's compound library resulted in the identification of weak Acetyl-CoA Carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.