title: Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain.
abstract: Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., Cambridge, Massachusetts 02142, United States. hbregman@amgen.com
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: Loren
authors.initials: L
authors.lastname: Berry
authors.forename: John L
authors.initials: JL
authors.lastname: Buchanan
authors.forename: April
authors.initials: A
authors.lastname: Chen
authors.forename: Bingfan
authors.initials: B
authors.lastname: Du
authors.forename: Elma
authors.initials: E
authors.lastname: Feric
authors.forename: Markus
authors.initials: M
authors.lastname: Hierl
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Immke
authors.forename: Brett
authors.initials: B
authors.lastname: Janosky
authors.forename: Danielle
authors.initials: D
authors.lastname: Johnson
authors.forename: Xingwen
authors.initials: X
authors.lastname: Li
authors.forename: Joseph
authors.initials: J
authors.lastname: Ligutti
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Annika
authors.initials: A
authors.lastname: Malmberg
authors.forename: David
authors.initials: D
authors.lastname: Matson
authors.forename: Jeff
authors.initials: J
authors.lastname: McDermott
authors.forename: Peter
authors.initials: P
authors.lastname: Miu
authors.forename: Hanh Nho
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Daniel
authors.initials: D
authors.lastname: Waldon
authors.forename: Ben
authors.initials: B
authors.lastname: Wilenkin
authors.forename: Xiao Mei
authors.initials: XM
authors.lastname: Zheng
authors.forename: Anruo
authors.initials: A
authors.lastname: Zou
authors.forename: Stefan I
authors.initials: SI
authors.lastname: McDonough
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005557:Formaldehyde; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015222:Sodium Channels; D012995:Solubility; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000700:Analgesics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C561228:N-(2-methyl-3-(4-(4-(4-(trifluoromethoxy)benzyloxy)piperidin-1-yl)-1,3,5-triazin-2-ylamino)phenyl)acetamide; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014227:Triazines; D005557:Formaldehyde; D013779:Tetrodotoxin