Journal of Medicinal Chemistry p. 935 - 942 (2012)
Update date:2022-08-02
Topics:
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
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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