Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors
Paul A. Barsanti(Novartis (United States)), Yue Pan(Novartis (United States)), Yipin Lu(Novartis (United States)), Rama Jain(Novartis (United States)), Matthew Cox(Novartis (United States)), Robert J. Aversa(Novartis (United States)), Michael P. Dillon(Novartis (United States)), R.A. Elling(Novartis (United States)), Cheng Hu(Novartis (United States)), Xianming Jin(Novartis (United States)), Mark Knapp(Novartis (United States)), Jiong Lan(Novartis (United States)), Savithri Ramurthy(Novartis (United States)), Patrick J. Rudewicz(Novartis (United States)), L Setti(Novartis (United States)), Sharadha Subramanian(Novartis (United States)), Michelle Mathur(Novartis (United States)), Lorena Taricani(Novartis (United States)), George Thomas(Novartis (United States)), Linda Xiao(Novartis (United States)), Qin Yue(Novartis (United States))
Cited by 27Open Access
Abstract
Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered.
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