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
  • 1. Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. [email protected]
PMID: 22209205 DOI: 10.1016/j.bmcl.2011.11.111
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.

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