Dihydropyrazolopyrimidines containing benzimidazoles as KV1.5 potassium channel antagonists

Dihydropyrazolopyrimidines with a C6 heterocycle substituent were found to have high potency for block of KV1.5. 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 KV1.5 block of 0.030 μM without significant block of other cardiac ion channels. This compound also showed good bioavailability in rats and robust pharmacodynamic effects in a rabbit model.

KV1.5 blockers have the potential to be selective agents for the treatment of atrial fibrillation. Dihydropyrazolopyrimidines provide a template for the synthesis of potent and selective KV1.5 blockers.Figure optionsDownload as PowerPoint slide