Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives

Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives

A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with impr...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6812-6815
Hauptverfasser: Kort, Michael E, Atkinson, Robert N, Thomas, James B, Drizin, Irene, Johnson, Matthew S, Secrest, Matthew A, Gregg, Robert J, Scanio, Marc J C, Shi, Lei, Hakeem, Ahmed H, Matulenko, Mark A, Chapman, Mark L, Krambis, Michael J, Liu, Dong, Shieh, Char-Chang, Zhang, XuFeng, Simler, Gricelda, Mikusa, Joseph P, Zhong, Chengmin, Joshi, Shailen, Honore, Prisca, Roeloffs, Rosemarie, Werness, Stephen, Antonio, Brett, Marsh, Kennan C, Faltynek, Connie R, Krafte, Douglas S, Jarvis, Michael F, Marron, Brian E
Format: Artikel
Sprache:eng
Schlagworte:
Administration, Oral
Animals
Biological Availability
Niacinamide - chemistry
Niacinamide - pharmacokinetics
Niacinamide - pharmacology
Rats
Sodium Channel Blockers - administration & dosage
Sodium Channel Blockers - chemistry
Sodium Channel Blockers - pharmacokinetics
Sodium Channel Blockers - pharmacology
Structure-Activity Relationship
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Zusammenfassung:A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2010.08.121