Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid.
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.
Shimshoni
Jakob Avi
JA
Department of Pharmaceutics and Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, and the David R. Bloom Centre for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Bialer
Meir
M
Wlodarczyk
Bogdan
B
Finnell
Richard H
RH
Yagen
Boris
B
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D017029:Epilepsy, Complex Partial / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
D000927:Anticonvulsants; D014635:Valproic Acid; D014508:Urea