Referenced in: none

Automatically associated channels: Kv11.1

Title: 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 as a potent and selective I(Kur) inhibitor.

Authors: 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

Journal, date & volume: J. Med. Chem., 2012 Apr 12 , 55, 3036-48

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22409629

Abstract
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.