title: Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship.
abstract: Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.
authors.affiliation: Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. istvan.macsari@astrazeneca.com
authors.forename: Istvan
authors.initials: I
authors.lastname: Macsari
authors.forename: Lars
authors.initials: L
authors.lastname: Sandberg
authors.forename: Yevgeni
authors.initials: Y
authors.lastname: Besidski
authors.forename: Ylva
authors.initials: Y
authors.lastname: Gravenfors
authors.forename: Tobias
authors.initials: T
authors.lastname: Ginman
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Tjerk
authors.initials: T
authors.lastname: Bueters
authors.forename: Anders B
authors.initials: AB
authors.lastname: Eriksson
authors.forename: Per-Eric
authors.initials: PE
authors.lastname: Lund
authors.forename: Elisabet
authors.initials: E
authors.lastname: Venyike
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D007260:Infusion Pumps; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D051381:Rats; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D007555:Isoxazoles; D026941:Sodium Channel Blockers