title: Synthesis and evaluation of antiallodynic and anticonvulsant activity of novel amide and urea derivatives of valproic acid analogues.
abstract: Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED(50) values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Kaufmann
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Jakob Avi
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004597:Electroshock; D007536:Isomerism; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013127:Spinal Nerves; D014508:Urea / Q000031:analogs & derivatives*; D014635:Valproic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; D014635:Valproic Acid; D014508:Urea; D010433:Pentylenetetrazole