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.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. heather.finlay@bms.com
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Finlay
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: Alexander
authors.initials: A
authors.lastname: Kover
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Gauri
authors.initials: G
authors.lastname: Bhave
authors.forename: Joseph
authors.initials: J
authors.lastname: Prol
authors.forename: Tram
authors.initials: T
authors.lastname: Huynh
authors.forename: Rao
authors.initials: R
authors.lastname: Bhandaru
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Caringal
authors.forename: John
authors.initials: J
authors.lastname: DiMarco
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Tim
authors.initials: T
authors.lastname: Harper
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Conder
authors.forename: Huabin
authors.initials: H
authors.lastname: Sun
authors.forename: Paul
authors.initials: P
authors.lastname: Levesque
authors.forename: Michael
authors.initials: M
authors.lastname: Blanar
authors.forename: Karnail
authors.initials: K
authors.lastname: Atwal
authors.forename: Ruth
authors.initials: R
authors.lastname: Wexler
mesh_terms: D000818:Animals; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C574632:(5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo(1,5-a)pyrimidin-6-yl)(2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone; D051666:Kv1.5 Potassium Channel; D011720:Pyrazoles; D011743:Pyrimidines