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

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

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

Bioorg Med Chem. 2008 Jun 15;16(12):6379-86. doi: 10.1016/j.bmc.2008.05.003. Epub 2008 May 6.

PubMed ID

18501613 [ View in PubMed

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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 Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Lamotrigine	Voltage-gated sodium channel alpha subunit	IC 50 (nM)	10000	N/A	N/A	Details
Mexiletine	Sodium channel protein type 5 subunit alpha	IC 50 (nM)	13000	N/A	N/A	Details