Discovery of ((S)-5-(Methoxymethyl)-7-(1-methyl-1 H-indol-2-yl)-2-(trifluoromethyl)-4, 7-dihydropyrazolo [1, 5-a] pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl) pyrrolidin- …

…, J Prol, T Huynh, R Bhandaru, Y Caringal…

文献索引：Finlay, Heather J.; Lloyd, John; Vaccaro, Wayne; Kover, Alexander; Yan, Lin; Bhave, Gauri; Prol, Joseph; Huynh, Tram; Bhandaru, Rao; Caringal, Yolanda; Dimarco, John; Gan, Jinping; Harper, Tim; Huang, Christine; Conder, Mary Lee; Sun, Huabin; Levesque, Paul; Blanar, Michael; Atwal, Karnail; Wexler, Ruth Journal of Medicinal Chemistry, 2012 , vol. 55, # 7 p. 3036 - 3048

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被引用次数: 9

摘要

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of IKur current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent IKur inhibitors, with selectivity over h ERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead ...