Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.
Bioorg Med Chem Lett
; 22(2): 1055-60, 2012 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-22209205
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinonas
/
Canais de Sódio
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Ano de publicação:
2012
Tipo de documento:
Article