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Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies

2006; Elsevier BV; Volume: 16; Issue: 16 Linguagem: Inglês

10.1016/j.bmcl.2006.05.092

1464-3405

Xiaodong Lin, Jeremy Murray, Alice Rico, Michael Wang, Daniel T. W. Chu, Yasheen Zhou, Merci Del Rosario, Susan Kaufman, Sylvia Ma, Eric Fang, Kenneth Crawford, Anne B. Jefferson,

Chemical synthesis and pharmacological studies

A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.