title: Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice.
abstract: 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.
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, Japan. akinobu.okada@us.astellas.com
authors.forename: Akinobu
authors.initials: A
authors.lastname: Okada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Noyori
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Jakob Avi
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Michio
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: 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*
chemical_list: D000927:Anticonvulsants; D013723:Teratogens; D014635:Valproic Acid; D014508:Urea; D010433:Pentylenetetrazole