title: Alpha-fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide, a novel potent anticonvulsant derivative of a cyclic analogue of valproic acid.
abstract: 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, 4) is a cyclic analogue of the antiepileptic drug (AED) valproic acid (VPA) (1). alpha-F, alpha-Cl, alpha-Br, and alpha-methyl derivatives of 4 and their amides were synthesized and tested in rodent models for anticonvulsant potency and AED-induced teratogenicity. In the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol (scMet) tests, alpha-Cl-TMCD (17) had ED(50) values of 97 and 27 mg/kg, respectively. alpha-F-TMCD (11) was 120 times more potent than VPA in the rat-scMet test (ED(50) = 6 mg/kg) and had a protective index (PI = TD(50)/ED(50)) of 20. In the 6 Hz psychomotor mouse model 11 had ED(50) values of 57 mg/kg (32 mA) and 59 mg/kg (44 mA). The ED(50) values of 11 in the hippocampal-kindled rat model and in the pilocarpine-induced-status rat model were 30 and 23 mg/kg, respectively. Unlike 1, 11 was nonteratogenic in mice. This novel compound has the potential to become a candidate for development as a new potent and safe antiepileptic and CNS drug.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, and The David R. Bloom Centre for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Pessah
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D003521:Cyclopropanes; C540329:alpha-fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide; C033650:2,2,3,3-tetramethylcyclopropanecarboxylic acid; D014635:Valproic Acid