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-1-yl)methanone as a potent and selective I _(Kur) inhibitor

摘要

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I _(Kur) 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 I _(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol- 2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S) -2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.