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
| Autor: | Huabin Sun, Joseph Prol, Karnail S. Atwal, T.W. Harper, Yolanda Caringal, Michael A. Blanar, Ruth R. Wexler, Jinping Gan, Christine Huang, Wayne Vaccaro, Alexander Kover, Paul Levesque, Heather Finlay, Lin Yan, John Lloyd, John D. Dimarco, Mary Lee Conder, Tram N. Huynh, Bhandaru Rao S, Gauri Bhave |
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| Rok vydání: | 2012 |
| Předmět: |
Refractory Period
Electrophysiological Stereochemistry hERG Stereoisomerism chemistry.chemical_compound Kv1.5 Potassium Channel Structure-Activity Relationship Dogs Drug Discovery Potency Structure–activity relationship Animals Humans Trifluoromethyl biology Heart In vitro Rats Pyrimidines chemistry Reactive metabolite biology.protein Molecular Medicine Pyrazoles Rabbits Selectivity |
| Zdroj: | Journal of medicinal chemistry. 55(7) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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