New research, 'Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice,' is the subject of a report. "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," scientists writing in the journal Birth Defects Research Part B, Developmental and Reproductive Toxicology report (see also Central Nervous System Disorders Therapy).

"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. 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. 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," wrote A. Okada and colleagues, Astellas Pharma, Inc.

The researchers concluded: "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 and colleagues published their study in Birth Defects Research Part B, Developmental and Reproductive Toxicology (Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice. Birth Defects Research Part B, Developmental and Reproductive Toxicology, 2009;86(5):394-401).

Additional information can be obtained by contacting A. Okada, Drug Safety Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, Japan.

The publisher of the journal Birth Defects Research Part B, Developmental and Reproductive Toxicology can be contacted at: Blackwell Publishing Inc., 350 Main St., Malden, MA 02148, USA.