Discovery of novel and orally active NR2B-selective N-methyl-d-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity
| Autor: | Miyako Matsumizu, Hirohisa Shimokawa, Makoto Kawai, Hirotaka Tanaka, Hiroshi Nakamura, Mitsuhiro Kawamura, Ando Kazuo, Isao Sakurada, Kazunari Hattori, Seiji Nukui, Atsuko Ohta, Atsushi Omura |
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| Rok vydání: | 2007 |
| Předmět: |
N-Methylaspartate
Pyridines Stereochemistry medicine.drug_class Clinical Biochemistry hERG Administration Oral Pharmaceutical Science Dofetilide Carboxamide Receptors N-Methyl-D-Aspartate Biochemistry Chemical synthesis Inhibitory Concentration 50 Structure-Activity Relationship In vivo Drug Discovery medicine Molecular Biology Molecular Structure biology Chemistry Organic Chemistry Antagonist Receptor antagonist Ether-A-Go-Go Potassium Channels Solubility nervous system Drug Design biology.protein Molecular Medicine NMDA receptor medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 17:5533-5536 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2007.08.039 |
| Popis: | Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure–activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide 14e as an orally active NR2B-subtype selective N-methyl- d -aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC50 > 30 μM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose = 10 mg/kg, po). |
| Databáze: | OpenAIRE |
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