Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase

  • J Med Chem. 2012 Jan 26;55(2):935-42. doi: 10.1021/jm201503u.
Kevin D Freeman-Cook  1 ,  Paul Amor ,  Scott Bader ,  Leanne M Buzon ,  Steven B Coffey ,  Jeffrey W Corbett ,  Kenneth J Dirico ,  Shawn D Doran ,  Richard L Elliott ,  William Esler ,  Angel Guzman-Perez ,  Kevin E Henegar ,  Janet A Houser ,  Christopher S Jones ,  Chris Limberakis ,  Katherine Loomis ,  Kirk McPherson ,  Sharad Murdande ,  Kendra L Nelson ,  Dennis Phillion ,  Betsy S Pierce ,  Wei Song ,  Eliot Sugarman ,  Susan Tapley ,  Meihua Tu ,  Zhengrong Zhao
Affiliations
  • 1. Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. [email protected]
PMID: 22148323 DOI: 10.1021/jm201503u
Abstract

This paper describes the design and synthesis of a novel series of dual inhibitors of Acetyl-CoA Carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.