Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide.
N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.
Sobol
Eyal
E
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Yagen
Boris
B
Lamb
John G
JG
White
H Steve
HS
Wlodarczyk
Bogdan J
BJ
Finnell
Richard H
RH
Bialer
Meir
M
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003521:Cyclopropanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D009436:Neural Tube Defects / Q000139:chemically induced; D053284:Polyunsaturated Alkamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000517:prevention & control*; D014635:Valproic Acid / Q000031:analogs & derivatives*
D000927:Anticonvulsants; D003521:Cyclopropanes; C488793:N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide; D053284:Polyunsaturated Alkamides; D014635:Valproic Acid