Syntheses and Evaluation of Anticonvulsant Activity of Novel Branched Alkyl Carbamates
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- 作者：Naama Hen ; Meir Bialer ; Boris Yagen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：March 22, 2012
- 年：2012
- 卷：55
- 期：6
- 页码：2835-2845
- 全文大小：345K
- 年卷期：v.55,no.6(March 22, 2012)
- ISSN：1520-4804
文摘
A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl-carbamate (38) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED50 = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED50 = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy鈥搒afety profile and, consequently, are promising candidates for development as new antiepileptics.