Key result
Compound 13j was discovered as a potent and selective IKur inhibitor with an acceptable pharmacokinetic profile and efficacy in a preclinical rabbit atrial effective refractory period model.
Compound 13j is a novel, potent, and selective I(Kur) inhibitor with favorable pharmacokinetic and safety profiles in preclinical models, representing a potential candidate for atrial fibrillation therapy.
Supports advancement of selective IKur inhibitors; leaves open translation of rabbit efficacy to human AF.
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.
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Finlay et al. (2012) studied this question. ((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) was evaluated on Efficacy in the preclinical rabbit atrial effective refractory period (AERP) model. Compound 13j was discovered as a potent and selective IKur inhibitor with an acceptable pharmacokinetic profile and efficacy in a preclinical rabbit atrial effective refractory period model.
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