New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?

Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders.
Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide.
At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.
AuthorsNina Isoherranen, Boris Yagen, Meir Bialer
JournalCurrent opinion in neurology (Curr Opin Neurol) Vol. 16 Issue 2 Pg. 203-11 (Apr 2003) ISSN: 1350-7540 [Print] England
PMID12644750 (Publication Type: Journal Article, Review)
Chemical References
  • Amides
  • Anticonvulsants
  • Valproic Acid
  • isovaleramide
  • dipropylacetamide
  • Amides (therapeutic use)
  • Anticonvulsants (adverse effects, chemistry, therapeutic use)
  • Bipolar Disorder (drug therapy)
  • Epilepsy (drug therapy)
  • Humans
  • Migraine Disorders (drug therapy)
  • Valproic Acid (adverse effects, analogs & derivatives, chemistry, therapeutic use)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: