Abstract
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.
MeSH terms
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Animals
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Atrial Fibrillation / drug therapy
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Cell Line
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Humans
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Kv1.5 Potassium Channel / antagonists & inhibitors*
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Kv1.5 Potassium Channel / metabolism
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Mice
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Potassium Channel Blockers / chemistry
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Potassium Channel Blockers / pharmacokinetics
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Potassium Channel Blockers / pharmacology*
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology*
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Pyrimidines / chemistry
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rabbits
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Rats
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Structure-Activity Relationship
Substances
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Kv1.5 Potassium Channel
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Potassium Channel Blockers
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Pyrazoles
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Pyrimidines
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pyrazole