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)me
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- 作者：Heather J. Finlay ; John Lloyd ; Wayne Vaccaro ; Alexander Kover ; Lin Yan ; Gauri Bhave ; Joseph Prol ; Tram Huynh ; Rao Bhandaru ; Yolanda Caringal ; John DiMarco ; Jinping Gan ; Tim Harper ; Christine Huang ; Mary Lee Conder ; Huabin Sun ; Paul Levesque ; Michael Blanar ; Karnail Atwal ; Ruth Wexler
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：55
- 期：7
- 页码：3036-3048
- 全文大小：465K
- 年卷期：v.55,no.7(April 12, 2012)
- ISSN：1520-4804
文摘
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.