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Bioorg Med Chem Lett. 2014 Sep 15;24(18):4397-4401. doi: 10.1016/j.bmcl.2014.08.017. Epub 2014 Aug 14.

The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7.

Author information

1
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: ssun@xenon-pharma.com.
2
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.

Abstract

The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.

KEYWORDS:

Benzenesulfonamide; Na(v)1.7; Pain; Sodium channel

PMID:
25176194
DOI:
10.1016/j.bmcl.2014.08.017
[Indexed for MEDLINE]

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