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Structure-based Drug Design of Novel, Potent and Selective Azabenzimidazoles (ABI) as ATR Inhibitors

Barsanti, Paul A. and Pan, Yue and Lu, Yipin and Jain, Rama and Cox, Matthew and Aversa, Robert and Dillon, Michael and Elling, Robert and Hu, Cheng and Jin, Jeff and Knapp, Mark and Lan, Jiong and Ramurthy, Savithri and Rudewicz, Patrick and Setti, Lina and Subramanian, Sharadha and Mathus, Michelle and Taricani, Lorena and Thomas, George and Xiao, Linda and Yue, Qin (2015) Structure-based Drug Design of Novel, Potent and Selective Azabenzimidazoles (ABI) as ATR Inhibitors. ACS Medicinal Chemistry Letters, 6 (1). pp. 42-46. ISSN 1948-58751948-5875

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. 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 solved most of the various medicinal chemistry issues encountered.

Item Type: Article
Keywords: ATR, structure based drug design, CYP3A4 TDI, aldehyde oxidase
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/22940

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