2. Academic Validation
  3. Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase

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

Affiliation

  • 1 Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. kevin.freeman-cook@pfizer.com
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.

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