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Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives

Kort, ME., Atkinson, RN., Thomas, J., Drizin, I., Johnson, MS., Secrest, MA., Gregg, RJ., Scanio, MJC., Shi, L., Hakeem, AH., Matulenko, MA., Chapman, ML., Krambis, MJ., Liu, D., Shieh, CC., Zhang, XF., Simler, G., Mikusa, JP., Zhong, C., ... Marron, BE. (2010). Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives. Bioorganic and Medicinal Chemistry Letters, 20(22), 6812-6815. https://doi.org/10.1016/j.bmcl.2010.08.121

Abstract

A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Nav1.8 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.

10.1016/j.bmcl.2010.08.121

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