title: Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke.
abstract: In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Mitsubishi Tanabe Pharma Co., Ltd., 1000 Kamoshidacho, Aoba-ku, Yokohama, 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: Yukio
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Aki
authors.initials: A
authors.lastname: Soejima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimada
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nonaka
mesh_terms: D019840:2-Propanol / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy*
chemical_list: D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D019840:2-Propanol