Discovery of a novel class of benzazepinone Na(v)1.7 blockers: potential treatments for neuropathic pain

Scott B Hoyt; Clare London; David Gorin; Matthew J Wyvratt; Michael H Fisher; Catherine Abbadie; John P Felix; Maria L Garcia; Xiaohua Li; Kathryn A Lyons; Erin McGowan; D Euan MacIntyre; William J Martin; Birgit T Priest; Amy Ritter; McHardy M Smith; Vivien A Warren; Brande S Williams; Gregory J Kaczorowski; William H Parsons

doi:10.1016/j.bmcl.2007.05.076

Discovery of a novel class of benzazepinone Na(v)1.7 blockers: potential treatments for neuropathic pain

Bioorg Med Chem Lett. 2007 Aug 15;17(16):4630-4. doi: 10.1016/j.bmcl.2007.05.076. Epub 2007 May 27.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. scott_hoyt@merck.com

PMID: 17588748
DOI: 10.1016/j.bmcl.2007.05.076

Abstract

A series of benzodiazepines and benzazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of the benzazepinone series, compound 47, displayed potent, state-dependent block of hNa(v)1.7, and was orally efficacious in a rat model of neuropathic pain.

MeSH terms

Animals
Heterocyclic Compounds, 3-Ring / administration & dosage
Heterocyclic Compounds, 3-Ring / chemistry*
Heterocyclic Compounds, 3-Ring / pharmacology
Heterocyclic Compounds, 3-Ring / therapeutic use*
Molecular Structure
NAV1.7 Voltage-Gated Sodium Channel
Pain / drug therapy*
Rats
Sodium Channel Blockers / chemistry
Sodium Channel Blockers / classification*
Sodium Channel Blockers / pharmacology*
Sodium Channel Blockers / therapeutic use
Sodium Channels / metabolism*
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 3-Ring
NAV1.7 Voltage-Gated Sodium Channel
Scn9a protein, rat
Sodium Channel Blockers
Sodium Channels