title: Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke.
abstract: A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama 227-0033, Japan. Seki.Maki@ma.mt-pharma.co.jp
authors.forename: Maki
authors.initials: M
authors.lastname: Seki
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsuruta
authors.forename: Ryo
authors.initials: R
authors.lastname: Tatsumi
authors.forename: Aki
authors.initials: A
authors.lastname: Soejima
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D026941:Sodium Channel Blockers