Syntheses and Evaluation of Anticonvulsant Profile and Teratogenicity of Novel Amide Derivatives of Branched Aliphatic Carboxylic Acids with 4-Aminobenzensulfonamide

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• 作者：Naama Hen ; Meir Bialer ; Bogdan Wlodarczyk ; Richard H. Finnell ; Boris Yagen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：4177-4186
• 全文大小：987K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide were synthesized and evaluated in the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol seizure (scMet) tests. Fourteen of the synthesized amides had an anticonvulsant ED₅₀ of <50 mg/kg in the rat-MES test. The amides 2-methyl-N-(4-sulfamoylphenyl)butyramide (10), 2-ethyl-N-(4-sulfamoylphenyl)butyramide (11), and 3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide (15) were the most potent compounds possessing MES-ED₅₀ values of 7.6, 9.9, and 9.4 mg/kg and remarkable protective index (PI = TD₅₀/ED₅₀) values of 65.7, 50.5, and 53.2, respectively. These potent sulfanylamides caused neural tube defects only at doses markedly exceeding their effective dose. The anticonvulsant properties of these compounds make them potential candidates for further development as new, potent, and safe AEDs.