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Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain |
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| Authors: | Drizin Irene Gregg Robert J Scanio Marc J C Shi Lei Gross Michael F Atkinson Robert N Thomas James B Johnson Matthew S Carroll William A Marron Brian E Chapman Mark L Liu Dong Krambis Michael J Shieh Char-Chang Zhang XuFeng Hernandez Gricelda Gauvin Donna M Mikusa Joseph P Zhu Chang Z Joshi Shailen Honore Prisca Marsh Kennan C Roeloffs Rosemarie Werness Stephen Krafte Douglas S Jarvis Michael F Faltynek Connie R Kort Michael E |
| Affiliation: | Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. irene.drizin@abbott.com |
| 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. |
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