Discovery and synthesis of tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers.
A novel class of tetrahydroindolone-derived semicarbazones has been discovered as potent Kv1.5 blockers. In in vitro studies, several compounds exhibited very good potency for blockade of Kv1.5. Compound 8i showed good selectivity for blockade of Kv1.5 vs hERG and L-type calcium channels. In an anesthetized pig model, compounds 8i and 10c increased atrial ERP about 28%, 18%, respectively, in the right atrium without affecting ventricular ERP.
Wu
Shengde
S
Procter & Gamble Pharmaceuticals, Mason Business Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA. wu.s.3@pg.com
Fluxe
Andrew
A
Janusz
John M
JM
Sheffer
James B
JB
Browning
Greg
G
Blass
Benjamin
B
Cobum
Keith
K
Hedges
Richard
R
Murawsky
Michael
M
Fang
Bin
B
Fadayel
Gina M
GM
Hare
Michelle
M
Djandjighian
Laurent
L
D000818:Animals; D020746:Calcium Channels, L-Type / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000494:pharmacology; D019054:Evoked Potentials, Motor / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D009483:Neuropsychological Tests; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D012664:Semicarbazones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
D020746:Calcium Channels, L-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D012664:Semicarbazones