Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

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• 作者：Jakob Avi Shimshoni ; Meir Bialer ; Bogdan Wlodarczyk ; Richard H. Finnell ; Boris Yagen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：December 13, 2007
• 年：2007
• 卷：50
• 期：25
• 页码：6419 - 6427
• 全文大小：134K
• 年卷期：v.50,no.25(December 13, 2007)
• ISSN：1520-4804

文摘

Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.