title: 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.
abstract: 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.
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. yong-jin.wu@bms.com
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Wu
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Sun
authors.forename: Huan
authors.initials: H
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: John E
authors.initials: JE
authors.lastname: Starrett
authors.forename: Pierre
authors.initials: P
authors.lastname: Dextraze
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Daris
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Boissard
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.forename: Valentin K
authors.initials: VK
authors.lastname: Gribkoff
authors.forename: Joanne
authors.initials: J
authors.lastname: Natale
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.forename: David G
authors.initials: DG
authors.lastname: Harden
authors.forename: Mark W
authors.initials: MW
authors.lastname: Thompson
authors.forename: William
authors.initials: W
authors.lastname: Fitzpatrick
authors.forename: David
authors.initials: D
authors.lastname: Weaver
authors.forename: Dedong
authors.initials: D
authors.lastname: Wu
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Steven I
authors.initials: SI
authors.lastname: Dworetzky
mesh_terms: 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
chemical_list: D000178:Acrylamides; D001572:Benzofurans; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C496915:Kcnq2 protein, rat; D024642:Potassium Channels, Voltage-Gated