PubMed 22209205

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kv11.1 , Nav1.7

Title: Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.

Authors: Hanh Nho Nguyen, Howie Bregman, John L Buchanan, Bingfan Du, Elma Feric, Liyue Huang, Xingwen Li, Joseph Ligutti, Dong Liu, Annika B Malmberg, David J Matson, Jeff S McDermott, Vinod F Patel, Ben Wilenkin, Anruo Zou, Stefan I McDonough, Erin F DiMauro

Journal, date & volume: Bioorg. Med. Chem. Lett., 2012 Jan 15 , 22, 1055-60

PubMed link:

Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.