α-Fluoro-2,2,3,3-Tetramethylcyclopropanecarboxamide, a Novel Potent Anticonvulsant Derivative of a Cyclic Analogue of Valproic Acid

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• 作者：Neta Pessah ; Meir Bialer ; Bogdan Wlodarczyk ; Richard H. Finnell ; Boris Yagen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2233-2242
• 全文大小：199K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). α-F, α-Cl, α-Br, and α-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, α-Cl-TMCD (17) had ED₅₀ values of 97 and 27 mg/kg, respectively. α-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED₅₀ = 6 mg/kg) and had a protective index (PI = TD₅₀/ED₅₀) of 20. In the 6 Hz psychomotor mouse model 11 had ED₅₀ values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED₅₀ values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.