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 0.030muM without significant block of other cardiac ion channels. This compound also showed good bioavailability in rats and robust pharmacodynamic effects in a rabbit model.
Lloyd
John
J
Bristol-Myers Squibb, Pharmaceutical Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. john.lloyd@bms.com
Finlay
Heather J
HJ
Atwal
Karnail
K
Kover
Alexander
A
Prol
Joseph
J
Yan
Lin
L
Bhandaru
Rao
R
Vaccaro
Wayne
W
Huynh
Tram
T
Huang
Christine S
CS
Conder
Marylee
M
Jenkins-West
Tonya
T
Sun
Huabin
H
Li
Danshi
D
Levesque
Paul
P
D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy; D002460:Cell Line; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011743:Pyrimidines; C031280:pyrazole