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Structure based drug design of novel potent and selective tetrahydropyrazolo[1,5-a]pyrazines as ATR inhibitors

Barsanti, Paul and Aversa, Robert and Jin, Jeff and Pan, Yue and Lu, Yipin and Elling, Robert and Jain, Rama and Knapp, Mark and Lin, Xiaodong and Rudewicz, Patrick and Sim, Janet and Taricani, Lorena and Thomas, George and Xiao, Linda and Yue, Qin (2015) Structure based drug design of novel potent and selective tetrahydropyrazolo[1,5-a]pyrazines as ATR inhibitors. ACS Medicinal Chemistry Letters, 6 (1). pp. 37-41. ISSN 1948-58751948-5875

Abstract

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Ka mutants as ATR crystal structure surrogates were instrumental in providing co-crystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium labelled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.

Item Type: Article
Keywords: ATR, structure based drug design, Fsp3, deuterium, CYP3A4 TDI
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/22793

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