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Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors.

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 PI3K? 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.

SUBMITTER: Barsanti PA

PROVIDER: S-EPMC4291715 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors.

Barsanti Paul A PA Aversa Robert J RJ Jin Xianming X Pan Yue Y Lu Yipin Y Elling Robert R Jain Rama R Knapp Mark M Lan Jiong J Lin Xiaodong X Rudewicz Patrick P Sim Janet J Taricani Lorena L Thomas George G Xiao Linda L Yue Qin Q

ACS medicinal chemistry letters 20141120 1

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 ...[more]

PMID: 25589927

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