Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors

Yong-Jin Wu; Jason Guernon; Andrea McClure; Brian Venables; Ramkumar Rajamani; Kevin J Robbins; Ronald J Knox; Michele Matchett; Rick L Pieschl; James Herrington; Linda J Bristow; Nicholas A Meanwell; Richard Olson; Lorin A Thompson; Carolyn Dzierba

doi:10.1016/j.bmcl.2018.01.035

Discovery of morpholine-based aryl sulfonamides as Na_v1.7 inhibitors

Bioorg Med Chem Lett. 2018 Mar 1;28(5):958-962. doi: 10.1016/j.bmcl.2018.01.035. Epub 2018 Feb 1.

Authors

Affiliations

¹ Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: [email protected].
² Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.

PMID: 29439904
DOI: 10.1016/j.bmcl.2018.01.035

Abstract

Replacement of the piperidine ring in the lead benzenesulfonamide Na_v1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Na_v1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Na_v1.7 inhibitors. This report describes the synthesis and SAR of these analogs.

Keywords: Aryl sulfonamides; Morpholine-based; Na(v)1.7 inhibitor; Pain.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Morpholines / chemistry
Morpholines / pharmacology*
NAV1.7 Voltage-Gated Sodium Channel / metabolism*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Voltage-Gated Sodium Channel Blockers / chemical synthesis
Voltage-Gated Sodium Channel Blockers / chemistry
Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

Morpholines
NAV1.7 Voltage-Gated Sodium Channel
Sulfonamides
Voltage-Gated Sodium Channel Blockers
morpholine