414895-05-9Relevant academic research and scientific papers
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
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
, p. 3036 - 3048 (2012)
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 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.
Dihydropyrazolopyrimidine Inhibitors of KV1.5 (IKur)
Vaccaro, Wayne,Huynh, Tram,Lloyd, John,Atwal, Karnail,Finlay, Heather J.,Levesque, Paul,Conder, Mary Lee,Jenkins-West, Tonya,Shi, Hong,Sun, Lucy
experimental part, p. 6381 - 6385 (2009/09/06)
A series of dihydropyrazolopyrimidine inhibitors of KV1.5 (IKur) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described.
