Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines
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- 作者：Hong Lin ; Dennis S. Yamashita ; Ren Xie ; Jin Zeng ; Wenyong Wang ; Jack Leber ; Igor G. Safonov ; Sharad Verma ; Mei Li ; Louis LaFrance ; Joseph Venslavsky ; Dennis Takata ; Juan I. Luengo ; Jason A. Kahana ; Sh
- 关键词：AKT kinase inhibitors ; Aminopyridines
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2010
- 出版时间：15 January 2010
- 年：2010
- 卷：20
- 期：2
- 页码：684-688
- 全文大小：780 K
文摘
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 GSK3β and tumor growth in a BT474 tumor xenograft model in mice.