Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

James B. Thomas; I Drizin; RJ Gregg; MJC Scanio; L Shi; MF Gross; RN Atkinson; James B. Thomas; MS Johnson; WA Carroll; BE Marron; ML Chapman; D Liu; MJ Krambis; CC Shieh; XF Zhang; G Hernandez; DM Gauvin; JP Mikusa; CZ Zhu; S Joshi; P Honore; KC Marsh; R Roeloffs; S Werness; DS Krafte; MF Jarvis; CR Faltynek; ME Kort

Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

Drizin, I., Gregg, RJ., Scanio, MJC., Shi, L., Gross, MF., Atkinson, RN., Thomas, J., Johnson, MS., Carroll, WA., Marron, BE., Chapman, ML., Liu, D., Krambis, MJ., Shieh, CC., Zhang, XF., Hernandez, G., Gauvin, DM., Mikusa, JP., Zhu, CZ., ... Kort, ME. (2008). Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain. Bioorganic and Medicinal Chemistry, 16(12), 6379-6386. https://doi.org/10.1016/j.bmc.2008.05.003

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Abstract

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Nav1.8 (PN3) as well as the Nav1.2 and Nav1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.