New Urea Derivatives of Valproic Acid as Anticonvulsants and for the Treatment of Pain, Migraines, and Bipolar Diseases

Background

Valproic acid (VPA) is a first line antiepileptic and CNS drug (Epilepsy, neuropathic pain, bipolar disorders etc)

• Multivalent action of VPA is highly advantageous, promising improved efficacy with reduced side effects for treatment of CNS diseases.
• Current the clinical use of VPA is limited at fertile women and children population due to potentially life-threatening side effects such as teratogenicity and hepatotoxicity
• These VPA derivatives demonstrated efficacy in animal models of neuropathic pain and bipolar disorder.

Our Innovation

• VPA urea analogues and derivatives with improved anticonvulsant activity while avoiding its teratogenicity and hepatotoxicity.
• Some of the VPA derivatives and analogues were also potent in animal models of neuropathic pain and bipolar disorder. 

wherein:

• R1-R4 are each independently hydrogen or an alkyl having from 1 to 10 carbon atoms; and
• Ra and Rb are each methyl,
• with the proviso that when each of R2-R4 is hydrogen, R1 is an alkyl having from 3 to 10 carbon atoms.

We found that the urea derivatives are much more potent as anticonvulsants and possess a higher protective index, than their corresponding acids.  Urea derivatives of valproic acid are very promising anticonvulsants possessing the potential in the treatment of mood disorders and migraine.

Pre-Clinical Results

A new and highly effective AED, 2,2,3,3-tetramethylcyclopropylcarbonylurea  (TMCU), has recently been synthesized and tested developed in our laboratory. TMCU showed activity in the scMet and MES-model tests in mice and rats, with a protective index (TD50-to-ED50 ratio) of 18.5 in the maximal electroshock (MES) test, compared to 1.6 for VPA.