title: Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship.
abstract: The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.
authors.affiliation: Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. inger.kers@astrazeneca.com
authors.forename: Inger
authors.initials: I
authors.lastname: Kers
authors.forename: Istvan
authors.initials: I
authors.lastname: Macsari
authors.forename: Gabor
authors.initials: G
authors.lastname: Csjernyik
authors.forename: Martin
authors.initials: M
authors.lastname: Nylöf
authors.forename: Karin
authors.initials: K
authors.lastname: Skogholm
authors.forename: Lars
authors.initials: L
authors.lastname: Sandberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Minidis
authors.forename: Tjerk
authors.initials: T
authors.lastname: Bueters
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmborg
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: Lei
authors.initials: L
authors.lastname: Luo
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Nyström
authors.forename: Yevgeni
authors.initials: Y
authors.lastname: Besidski
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers; D009536:Niacinamide