Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice.
BACKGROUND
Valproic acid (VPA) is used to treat epilepsy and bipolar disorders, as well as for migraine prophylaxis. However, its clinical use is limited by two life-threatening side effects: hepatotoxicity and teratogenicity. To develop a more potent and safer second-generation VPA drug, the urea derivatives of four VPA analogs (2-ethyl-3-methylpentanoyl urea, 2-ethylhexanoyl urea, 2-ethyl-4-methylpentanoyl urea, and 2-methylbutanoyl urea) were synthesized.


METHODS
Four CNS-active analogs of a VPA urea derivative testedthe anticonvulsant activity in the maximal electroshock seizure test (MES) and subcutaneous metrazol seizure threshold test (scMet). Teratogenic effects of these compounds were evaluated in NMRI mice susceptible to VPA-induced teratogenicity by comparison with VPA.


RESULTS
All four VPA analogs showed superior anticonvulsant activity over VPA. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at any concentration up to 4.8 mmol/kg (except for a single abnormality at 3.6 mmol/kg with 2-ethyl-3-methylpentanoyl urea). Skeletal examination also revealed that the acylurea derivatives induced vertebral and rib abnormalities in fetuses markedly less frequently than VPA. Our results confirmed that the analogue derivatives are significantly less teratogenic than VPA in NMRI mice.


CONCLUSIONS
The CNS-active VPA analogs containing a urea moiety, which have better anticonvulsant potency and lack teratogenicity, are good potential candidates as second-generation VPA antiepileptic drugs.
Okada
Akinobu
A
Drug Safety Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, Japan. akinobu.okada@us.astellas.com
Noyori
Hiroko
H
Yagen
Boris
B
Shimshoni
Jakob Avi
JA
Bialer
Meir
M
Fujiwara
Michio
M
D000014:Abnormalities, Drug-Induced; D000818:Animals; D000927:Anticonvulsants / Q000145:classification / Q000494:pharmacology / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D054810:Deep Sedation; D004056:Differential Threshold / Q000187:drug effects; D004558:Electric Stimulation; D004597:Electroshock / Q000009:adverse effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009436:Neural Tube Defects / Q000139:chemically induced; D010433:Pentylenetetrazole / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000145:classification / Q000494:pharmacology / Q000633:toxicity*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity*; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity*
D000927:Anticonvulsants; D013723:Teratogens; D014635:Valproic Acid; D014508:Urea; D010433:Pentylenetetrazole