Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives.
Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.
Department of Pharmaceutics, Faculty of Medicine, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel.
Eyal
E
Sobol
Meir
M
Bialer
Boris
B
Yagen
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003292:Convulsants; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004597:Electroshock; D051379:Mice; D010433:Pentylenetetrazole; D053284:Polyunsaturated Alkamides; D051381:Rats; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
C488794:2,2,3,3-tetramethylcyclopropanecarbonylurea; D000927:Anticonvulsants; D003292:Convulsants; D003521:Cyclopropanes; C488793:N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide; D053284:Polyunsaturated Alkamides; D014635:Valproic Acid; D014508:Urea; D010433:Pentylenetetrazole