四取代吡啶作为有效的、选择性的 AKT 抑制剂：氨基吡啶对 CYP450 和 hERG 的抑制作用降低。
Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines.
机构信息
Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States.
出版信息
Bioorg Med Chem Lett. 2010 Jan 15;20(2):684-8. doi: 10.1016/j.bmcl.2009.11.061. Epub 2009 Dec 16.
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
描述了一系列新型含氮茚并唑铰链结合物的四取代氨基吡啶的合成和评估，作为有效的 AKT 抑制剂。化合物 14c 被鉴定为一种有效的 AKT 抑制剂，与之前描述的三取代吡啶相比，其显示出降低的 CYP450 抑制作用和改善的可开发性特征。它还在 BT474 肿瘤异种移植模型的小鼠中显示出剂量依赖性的 GSK3β磷酸化和肿瘤生长抑制作用。
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