Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.
Journal: Bioorganic & Medicinal Chemistry
Published:
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.
Authors
Irene Drizin, Robert Gregg, Marc J Scanio, Lei Shi, Michael Gross, Robert Atkinson, James Thomas, Matthew Johnson, William Carroll, Brian Marron, Mark Chapman, Dong Liu, Michael Krambis, Char-chang Shieh, Xufeng Zhang, Gricelda Hernandez, Donna Gauvin, Joseph Mikusa, Chang Zhu, Shailen Joshi, Prisca Honore, Kennan Marsh, Rosemarie Roeloffs, Stephen Werness, Douglas Krafte, Michael Jarvis, Connie Faltynek, Michael Kort
Relevant Conditions