Synthesis and Evaluation of Antiallodynic and Anticonvulsant Activity of Novel Amide and Urea Derivatives of Valproic Acid Analogues

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• 作者：Dan Kaufmann ; Meir Bialer ; Jakob Avi Shimshoni ; Marshall Devor ; Boris Yagen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7236-7248
• 全文大小：871K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA’s clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED₅₀ values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain.