Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
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- 作者：Kevin D. Freeman-Cook ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：January 26, 2012
- 年：2012
- 卷：55
- 期：2
- 页码：935-942
- 全文大小：380K
- 年卷期：v.55,no.2(January 26, 2012)
- ISSN：1520-4804
文摘
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.