Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-<i>a</i>]pyrazines as ATR Inhibitors
Paul A. Barsanti(Novartis (United States)), Robert J. Aversa(Novartis (United States)), Xianming Jin(Novartis (United States)), Yue Pan(Novartis (United States)), Yipin Lu(Novartis (United States)), R.A. Elling(Novartis (United States)), Rama Jain(Novartis (United States)), Mark Knapp(Novartis (United States)), Jiong Lan(Novartis (United States)), Xiaodong Lin(Novartis (United States)), Patrick J. Rudewicz(Novartis (United States)), Janet Sim(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 41Open Access
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 PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.
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