(S,E)-N-[1-(3-heteroarylphenyl)ethyl]-3-(2-fluorophenyl)acrylamides: synthesis and KCNQ2 potassium channel opener activity.
Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.
L'Heureux
Alexandre
A
Department of Medicinal Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 de l'Industrie Blvd., Candiac, Quebec, Canada, J5R 1J1.
Martel
Alain
A
He
Huan
H
Chen
Jie
J
Sun
Li-Qiang
LQ
Starrett
John E
JE
Natale
Joanne
J
Dworetzky
Steven I
SI
Knox
Ronald J
RJ
Harden
David G
DG
Weaver
David
D
Thompson
Mark W
MW
Wu
Yong-Jin
YJ
D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051658:KCNQ2 Potassium Channel; D015394:Molecular Structure; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*
D000178:Acrylamides; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D024642:Potassium Channels, Voltage-Gated