Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides.
This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed. Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model.
Nanda
Kausik K
KK
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., PO Box 4, West Point, PA 19486, USA.
Nolt
M Brad
MB
Cato
Matthew J
MJ
Kane
Stefanie A
SA
Kiss
Laszlo
L
Spencer
Robert H
RH
Wang
Jixin
J
Lynch
Joseph J
JJ
Regan
Christopher P
CP
Stump
Gary L
GL
Li
Bing
B
White
Rebecca
R
Yeh
Suzie
S
Bogusky
Michael J
MJ
Bilodeau
Mark T
MT
Dinsmore
Christopher J
CJ
Lindsley
Craig W
CW
Hartman
George D
GD
Wolkenberg
Scott E
SE
Trotter
B Wesley
BW
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C515789:1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea; D000081:Acetamides; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D011725:Pyridines; D014508:Urea