Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides.
Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.
Wu
Yong-Jin
YJ
Department of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. yong-jin.wu@bms.com
Sun
Li-Qiang
LQ
He
Huan
H
Chen
Jie
J
Starrett
John E
JE
Dextraze
Pierre
P
Daris
Jean-Paul
JP
Boissard
Christopher G
CG
Pieschl
Rick L
RL
Gribkoff
Valentin K
VK
Natale
Joanne
J
Knox
Ronald J
RJ
Harden
David G
DG
Thompson
Mark W
MW
Fitzpatrick
William
W
Weaver
David
D
Wu
Dedong
D
Gao
Qi
Q
Dworetzky
Steven I
SI
D000178:Acrylamides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051658:KCNQ2 Potassium Channel; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D051381:Rats
D000178:Acrylamides; D001572:Benzofurans; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C496915:Kcnq2 protein, rat; D024642:Potassium Channels, Voltage-Gated