Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1652-6. doi: 10.1016/j.bmcl.2010.01.046. Epub 2010 Jan 20.
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
描述了一系列作为 AKT1 抑制剂的 2-氨基噻二唑类化合物。讨论了 SAR 关系，以及对蛋白激酶 A（PKA）和细胞周期蛋白依赖性激酶 2（CDK2）的选择性。通过 X 射线晶体学分析，合理地解释了几种化合物对 AKT1 与 PKA 的中度选择性。关键化合物在细胞测定中表现出对两种 AKT 底物 PRAS40 和 FKHRL1 的磷酸化的活性。化合物 30 被推进到小鼠肝 PD 测定中，在该测定中，它显示出 AKT 活性的剂量依赖性抑制，如通过抑制磷酸化 PRAS40 来测量。
