1. Academic Validation
  2. Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists

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

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):1055-60. doi: 10.1016/j.bmcl.2011.11.111.
Hanh Nho Nguyen 1 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
Affiliations

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. hanhn@amgen.com
Abstract

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.

Figures
Products