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Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Shimshoni JA,Bialer M,Wlodarczyk B,Finnell RH,Yagen B

doi

10.1021/jm7009233

subject

Has Abstract

pub_date

2007-12-13 00:00:00

pages

6419-27

issue

25

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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