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.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Dogs , Heart/drug effects , Heart/physiology , Humans , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rabbits , Rats , Refractory Period, Electrophysiological/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Design and synthesis of pyrazolodihydropyrimidines as KV1.5 blockers led to the discovery of 7d as a potent and selective antagonist. This compound showed atrial selective prolongation of effective refractory period in rabbits and was selected for clinical development.
Subject(s)
Amides/chemical synthesis , Kv1.5 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/chemical synthesis , Pyrazoles/pharmacology , Pyrrolidines/chemistry , Amides/chemistry , Amides/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Molecular Structure , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rabbits , RatsABSTRACT
Dihydropyrazolopyrimidines with a C6 heterocycle substituent were found to have high potency for block of K(V)1.5. Investigation of the substitution in the benzimidazole ring and the substituent in the 5-position of the dihydropyrazolopyrimidine ring produced 31a with an IC50 for K(V)1.5 block of 0.030muM without significant block of other cardiac ion channels. This compound also showed good bioavailability in rats and robust pharmacodynamic effects in a rabbit model.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Atrial Fibrillation/drug therapy , Cell Line , Humans , Kv1.5 Potassium Channel/metabolism , Mice , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.