Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives
Kort, M. E., Atkinson, R. N., Thomas, J., Drizin, I., Johnson, M. S., Secrest, M. A., ... Marron, B. E. (2010). Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives. Bioorganic and Medicinal Chemistry Letters, 20(22), 6812-6815. DOI: 10.1016/j.bmcl.2010.08.121
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.