Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid.
OBJECTIVE
The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA).


METHODS
The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats.


RESULTS
DBU emerged as the most potent compound having an MES-ED(50)of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED(50)of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED(50)= 35 mg/kg), the psychomotor 6 Hz mouse model (ED(50)= 80 mg/kg at 32 mA and ED(50)= 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED(50)= 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h.


CONCLUSIONS
DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.
Shimshoni
Jakob Avi
JA
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Yagen
Boris
B
Pessah
Neta
N
Wlodarczyk
Bogdan
B
Finnell
Richard H
RH
Bialer
Meir
M
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D004567:Electrodes, Implanted; D006207:Half-Life; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced; D010433:Pentylenetetrazole / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*
C530684:3,3-dimethylbutanoylurea; D000927:Anticonvulsants; D013723:Teratogens; D014635:Valproic Acid; D014508:Urea; D010433:Pentylenetetrazole