Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists
| Autor: | Elma Feric, Joseph Ligutti, Anruo Zou, Bingfan Du, Stefan I. McDonough, Dong Liu, Nagasree Chakka, Hanh Nho Nguyen, Erin F. DiMauro, John L. Buchanan, Howie Bregman, Jeff S. McDermott |
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| Rok vydání: | 2011 |
| Předmět: |
Stereochemistry
Clinical Biochemistry hERG Pharmaceutical Science Pain Biochemistry Pyrazolopyrimidine Sodium Channels chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Structure–activity relationship Humans Pyrroles Molecular Biology Sodium Channel Inhibitors biology Drug discovery Organic Chemistry NAV1.7 Voltage-Gated Sodium Channel Hit to lead Liver metabolism Pyrimidines chemistry State dependent biology.protein Microsomes Liver Molecular Medicine Sodium Channel Blockers |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(5) |
| ISSN: | 1464-3405 |
| Popis: | Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Na(v)1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na(v)1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts. |
| Databáze: | OpenAIRE |
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