title: Discovery of pyrrolo-benzo-1,4-diazines as potent Na(v)1.7 sodium channel blockers.
abstract: A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Ginny D
authors.initials: GD
authors.lastname: Ho
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Bercovici
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hanisak
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brumfield
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Julius
authors.initials: J
authors.lastname: Matasi
authors.affiliation: Department of Medicinal Chemistry, AMRI Global, Albany, NY 12203, United States.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Heap
authors.affiliation: Department of Medicinal Chemistry, AMRI Global, Albany, NY 12203, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Earley
authors.affiliation: Department of Medicinal Chemistry, AMRI Global, Albany, NY 12203, United States.
authors.forename: Brandy
authors.initials: B
authors.lastname: Courneya
authors.affiliation: Department of Medicinal Chemistry, AMRI Global, Albany, NY 12203, United States.
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.affiliation: In Vivo Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Cardiorenal Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Terry
authors.initials: T
authors.lastname: Bridal
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.affiliation: Cardiorenal Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Sorota
authors.affiliation: Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States. Electronic address: shu-wei.yang@merck.com.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Yang
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D011810:Quinoxalines; D026941:Sodium Channel Blockers; D013141:Spiro Compounds
keywords: Nav1.5; Nav1.7; Pain; Pyrrolo-benzo-1,4-diazine; Sodium channel blockers