Alpha-fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide, a novel potent anticonvulsant derivative of a cyclic analogue of valproic acid
| Autor: | Boris Yagen, Richard H. Finnell, Meir Bialer, Neta Pessah, Bogdan J. Wlodarczyk |
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| Rok vydání: | 2009 |
| Předmět: |
Cyclopropanes
Male medicine.drug_class medicine.medical_treatment Carboxamide Pharmacology Rats Sprague-Dawley Mice Structure-Activity Relationship Oral administration Drug Discovery medicine Pi Potency Animals ED50 Valproic Acid Epilepsy Chemistry Abnormalities Drug-Induced Rats Anticonvulsant Toxicity Molecular Medicine Anticonvulsants medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 52(8) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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