N-Aryl azacycles as novel sodium channel blockers

Stephen M Lynch; Laykea Tafesse; Kevin Carlin; Parijat Ghatak; Bin Shao; Haissam Abdelhamid; Donald J Kyle

doi:10.1016/j.bmcl.2014.11.023

N-Aryl azacycles as novel sodium channel blockers

Bioorg Med Chem Lett. 2015 Jan 1;25(1):48-52. doi: 10.1016/j.bmcl.2014.11.023. Epub 2014 Nov 14.

Authors

Stephen M Lynch¹, Laykea Tafesse², Kevin Carlin¹, Parijat Ghatak¹, Bin Shao¹, Haissam Abdelhamid¹, Donald J Kyle¹

Affiliations

¹ Discovery Research, Purdue Pharma L.P., 6 Cedarbrook Drive, Cranbury, NJ 08512, United States.
² Discovery Research, Purdue Pharma L.P., 6 Cedarbrook Drive, Cranbury, NJ 08512, United States. Electronic address: [email protected].

PMID: 25435147
DOI: 10.1016/j.bmcl.2014.11.023

Abstract

We have identified a new series of N-aryl azacycles as sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays. Analogs from this series possessed selectivity over hERG, reasonable oral exposure in rat PK studies and are predicted to have limited CNS penetration.

Keywords: Azacycle; Na(v)1.7; Neuropathic pain; Sodium channel.

MeSH terms

Amino Acid Sequence
Animals
Cell Membrane Permeability / drug effects
Cell Membrane Permeability / physiology
Dogs
Madin Darby Canine Kidney Cells
Molecular Sequence Data
NAV1.7 Voltage-Gated Sodium Channel / physiology*
Rats
Sodium Channel Blockers / chemical synthesis*
Sodium Channel Blockers / pharmacology

Substances

NAV1.7 Voltage-Gated Sodium Channel
Scn9a protein, rat
Sodium Channel Blockers