Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.
J Med Chem. 2012 Jan 26;55(2):935-42. doi: 10.1021/jm201503u. Epub 2012 Jan 11.
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.
本文描述了一系列新型乙酰辅酶 A 羧化酶 1 和 2（ACC1 和 ACC2）双重抑制剂的设计与合成。主要发现包括：发现了一个初始先导化合物，其活性中等，随后进行了药物化学优化，重点关注脂溶性效率（LipE）以平衡整体类药性。自由 - 威尔逊方法（Free-Wilson methodology）提供了一个明确的方法，可将特定结构元素对整体 LipE 的贡献进行细分，为虚拟化合物的合成提供了优先排序的依据，并对所得类似物的 LipE 进行了高度成功的预测。进一步的临床前研究，包括在大鼠肝脏（ACC1）和大鼠肌肉（ACC2）中体内丙二酰辅酶 A 的还原，鉴定出一种先进的类似物，该类似物进入了监管毒理学研究。
