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

…, W Esler, A Guzman-Perez, KE Henegar…

Index: Freeman-Cook, Kevin D.; Amor, Paul; Bader, Scott; Buzon, Leanne M.; Coffey, Steven B.; Corbett, Jeffrey W.; Dirico, Kenneth J.; Doran, Shawn D.; Elliott, Richard L.; Esler, William; Guzman-Perez, Angel; Henegar, Kevin E.; Houser, Janet A.; Jones, Christopher S.; Limberakis, Chris; Loomis, Katherine; McPherson, Kirk; Murdande, Sharad; Nelson, Kendra L.; Phillion, Dennis; Pierce, Betsy S.; Song, Wei; Sugarman, Eliot; Tapley, Susan; Tu, Meihua; Zhao, Zhengrong Journal of Medicinal Chemistry, 2012 , vol. 55, # 2 p. 935 - 942

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Citation Number: 19

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 ...