title: Synthesis and anticonvulsant activity of aromatic tetramethylcyclopropanecarboxamide derivatives.
abstract: As part of our ongoing research on potential new antiepileptic drugs (AEDs), a series of tetramethylcyclopropanecarboxamide derivatives containing benzene ring were designed, synthesized, and evaluated for anticonvulsant activities in the murine maximal electroshock (MES) and subcutaneous pentylenetetrazole (scMet) seizure tests. The most potent compound emerging from this study was N-(2,2,3,3-tetramethylcyclopropanecarboxamide)-p-phenyl-sulfonamide (21), possessing an ED(50) value of 26mg/kg in the rat-MES test and a remarkable PI (PI=TD(50)/ED(50)) value above 19. The better anticonvulsant potency of compound 21 and its wider safety margin compared to valproic acid (VPA) and zonisamide make it a potential candidate to become a new AED second-generation to VPA.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Jakob Avi
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000633:toxicity; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000633:toxicity; D004597:Electroshock; D007555:Isoxazoles / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D012640:Seizures / Q000188:drug therapy; D013449:Sulfonamides / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000633:toxicity; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity; D000078305:Zonisamide
chemical_list: C116673:2,2,3,3-tetramethylcyclopropane carboxamide; C488794:2,2,3,3-tetramethylcyclopropanecarbonylurea; D000577:Amides; D000927:Anticonvulsants; D003521:Cyclopropanes; D007555:Isoxazoles; D013449:Sulfonamides; D000078305:Zonisamide; D014635:Valproic Acid; D014508:Urea