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

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

Affiliation

  • 1 Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. jmc1983mac@gmail.com
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.

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