Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors

…, V Klinghofer, EK Han, R Guan, SR Magnone…

Index: Woods, Keith W.; Fischer, John P.; Claiborne, Akiyo; Li, Tongmei; Thomas, Sheela A.; Zhu, Gui-Dong; Diebold, Robert B.; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Han, Edward K.; Guan, Ran; Magnone, Shayna R.; Johnson, Eric F.; Bouska, Jennifer J.; Olson, Amanda M.; Jong, Ron de; Oltersdorf, Tilman; Luo, Yan; Rosenberg, Saul H.; Giranda, Vincent L.; Li, Qun Bioorganic and Medicinal Chemistry, 2006 , vol. 14, # 20 p. 6832 - 6846

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Citation Number: 62

Abstract

A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure–activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (Ki= 0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other ...