( S, E)- N-[1-(3-Heteroarylphenyl)ethyl]-3-(2-fluorophenyl)acrylamides: synthesis and KCNQ2 potassium channel opener activity

The synthesis and the KCNQ2 opener activity of a novel series of acrylamides are described. 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.