Design and synthesis of novel isoquinoline-3-nitriles as orally bioavailable Kv1.5 antagonists for the treatment of atrial fibrillation.
Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.
Trotter
B Wesley
BW
Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. bwesley_trotter@merck.com
Nanda
Kausik K
KK
Kett
Nathan R
NR
Regan
Christopher P
CP
Lynch
Joseph J
JJ
Stump
Gary L
GL
Kiss
Laszlo
L
Wang
Jixin
J
Spencer
Robert H
RH
Kane
Stefanie A
SA
White
Rebecca B
RB
Zhang
Rena
R
Anderson
Kenneth D
KD
Liverton
Nigel J
NJ
McIntyre
Charles J
CJ
Beshore
Douglas C
DC
Hartman
George D
GD
Dinsmore
Christopher J
CJ
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001682:Biological Availability; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D051666:Kv1.5 Potassium Channel; D009570:Nitriles