Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain
| Autor: | Shifeng Liu, Jianmin Fu, Rainbow Kwan, Ray Chui, Cadieux Jean-Jacques, Mikhail Chafeev, Vandna Raina, Wendy B. Young, Sultan Chowdhury, Jianyu Sun |
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| Rok vydání: | 2011 |
| Předmět: |
Indoles
Stereochemistry Clinical Biochemistry Pain Pharmaceutical Science Biochemistry Sodium Channels Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Sodium channel blocker Drug Discovery Humans Potency Structure–activity relationship Inhibitory concentration 50 Spiro Compounds Oxindole Molecular Biology Analgesics Molecular Structure NAV1.7 Voltage-Gated Sodium Channel Organic Chemistry Antagonist Oxindoles HEK293 Cells Gene Expression Regulation chemistry Lactam Molecular Medicine Lead compound |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:3676-3681 |
| ISSN: | 0960-894X |
| Popis: | Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts. |
| Databáze: | OpenAIRE |
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