期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 22, 期 2, 页码 1055-1060出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.11.111
关键词
Nav1.7; Voltage-gated sodium channels; Nav channels; Sodium channel blockers; Sodium channel inhibitors; Sodium channel antagonists; Congenital indifference to pain; Paroxysmal extreme pain disorder; Primary erythromelalgia; Aminopyrimidinone
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. (C) 2011 Elsevier Ltd. All rights reserved.
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