Dihydropyrazolopyrimidines containing benzimidazoles as K(V)1.5 potassium channel antagonists

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....

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (18), p.5469-5473
Main Authors: Lloyd, John, Finlay, Heather J, Atwal, Karnail, Kover, Alexander, Prol, Joseph, Yan, Lin, Bhandaru, Rao, Vaccaro, Wayne, Huynh, Tram, Huang, Christine S, Conder, Marylee, Jenkins-West, Tonya, Sun, Huabin, Li, Danshi, Levesque, Paul
Format: Article
Language:English
Subjects:
Animals
Atrial Fibrillation - drug therapy
Cell Line
Humans
Kv1.5 Potassium Channel - antagonists & inhibitors
Kv1.5 Potassium Channel - metabolism
Mice
Potassium Channel Blockers - chemistry
Potassium Channel Blockers - pharmacokinetics
Potassium Channel Blockers - pharmacology
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - pharmacology
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Rabbits
Rats
Structure-Activity Relationship
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Summary: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.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2009.07.083