title: Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain.
abstract: A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 μM.
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
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, Albany Molecular Research, Inc. (AMRI), Albany, NY 12203, United States.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, Albany Molecular Research, Inc. (AMRI), Albany, NY 12203, United States.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Sakwa
authors.affiliation: Department of Medicinal Chemistry, Albany Molecular Research, Inc. (AMRI), 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: Neuroscience, Merck Research Laboratory, West Point, PA 19486, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Urban
authors.affiliation: Neuroscience, Merck Research Laboratory, West Point, PA 19486, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vivian
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
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects*; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry*; D009437:Neuralgia / Q000188:drug therapy*; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000737:chemistry; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D013127:Spinal Nerves / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011810:Quinoxalines; D026941:Sodium Channel Blockers; D013141:Spiro Compounds
keywords: Na(v)1.5; Na(v)1.7; Pain; Sodium channel