, Volume 4, Issue 1, pp 130–137 | Cite as

Valproic acid: Second generation

  • Meir Bialer
  • Boris Yagen


The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

Key Words

Valproic acid analogs and derivatives of valproic acid second generation to valproic acid drugs antiepileptics and CNS drugs 


  1. 1.
    Bialer M, Johannessen SI, Kupferberg H, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: a summary of the seventh Eilat conference on new antiepileptic drugs (EILAT VII). Epilepsy Res 2004;61: 1–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Bialer M, Walker MC, Sander JWS. Pros and cons for the development of new antiepileptic drugs. CNS Drugs 2004;16: 285–289.CrossRefGoogle Scholar
  3. 3.
    Perucca E. The new antiepileptic drugs: pharmacological and clinical aspects. Curr Pharm Des 2000;6: 839–860.PubMedCrossRefGoogle Scholar
  4. 4.
    Bialer M. New antiepileptic drugs currently in clinical trials: is there a strategy in their development? Ther Drug Monit 2002;24: 85–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Walker MC, Sander JWS. The impact of new antiepileptic drugs on the prognosis of epilepsy: seizure freedom should be the ultimate goal. Neurology 1996;46: 912–914.PubMedGoogle Scholar
  6. 6.
    Isoherranen N, Yagen B, Bialer M. New CNS-active drugs which are second generation valproic acid: can they lead to development of the magic bullet? Curr Opin Neurol 2003;16: 203–211.PubMedCrossRefGoogle Scholar
  7. 7.
    Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Investig Drugs 2006;15: 637–647.PubMedCrossRefGoogle Scholar
  8. 8.
    Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 2006;69: 273–294.PubMedCrossRefGoogle Scholar
  9. 9.
    Perucca E. Pharmacological and therapeutic properties of valproate. A summary after 35 years of clinical experience. CNS Drugs 2002;16: 695–714.PubMedCrossRefGoogle Scholar
  10. 10.
    Loscher W. Valproate. Basel, Switzerland: Birkhauser Verlag; 1999.Google Scholar
  11. 11.
    Loscher W. Basic pharmacology of valproate. A review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 2002;16: 669–694.PubMedCrossRefGoogle Scholar
  12. 12.
    Peterson GM, Maunton M. Valproate: a simple chemical with so much to offer. J Clin Pharm Ther 2005;30: 417–421.PubMedCrossRefGoogle Scholar
  13. 13.
    Trojnar MK, Weirzchowska-Cioch E, Krzyzanowski M, Jargiello M, Czuzczwar SJ. New generation of valproic acid. Pol J Pharmacol 2004;56: 283–288.PubMedGoogle Scholar
  14. 14.
    Nau H, Hauck R-S, Ehlers K. Valproic acid induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol 1991;69: 310–321.PubMedCrossRefGoogle Scholar
  15. 15.
    Nau H, Siemens H. Differentiation between valproate-induced anticonvulsant effect, teratogenicity and hepatotoxicity. Pharm Weekbl Sci 1992;14: 101–107.PubMedGoogle Scholar
  16. 16.
    Nau H, Hendrickx AG. Valproic acid teratogenesis. ISI Atlas Sci Pharmacol 1987;1: 52–56.Google Scholar
  17. 17.
    Nau H, Loscher W. Pharmacological evaluations of various metabolites and analogs of valproic acid: teratogenic potencies in mice. Fundam Appl Toxicol 1986;6: 669–676.PubMedCrossRefGoogle Scholar
  18. 18.
    Tang W, Palaty J, Abbott FS. Time course of α-fluorinated valproic acid in mouse brain and serum and its effect on synaptosomal γ-aminobutyric acid levels in comparison to valproic acid. J Pharmacol Exp Ther 1997;282: 1163–1172.PubMedGoogle Scholar
  19. 19.
    Tang W, Borel AG, Fujimiya T, Abbott SF. Fluorinated analogues as mechanistic probes in valproic acid hepatotoxicity: hepatic microvesicular steatosis and glutathione status. Chem Res Toxicol 1995;8: 671–682.PubMedCrossRefGoogle Scholar
  20. 20.
    Neuman MG, Shear NH, Jacobson-Brown PM, et al. CYP2E1 mediated modulation of valproic acid-induced hepatocytotoxicity. Clin Biochem 2001;34: 211–218.PubMedCrossRefGoogle Scholar
  21. 21.
    Grillo MP, Chiellini G, Tonelli M, Benet LZ. Effect of alpha-fluorination of valproic acid on valproyl-S-acyl-CoA formation in vivo in rats. Drug Metab Dispos 2001;29: 1210–1215.PubMedGoogle Scholar
  22. 22.
    Isoherranen N, Yagen B, Blotnik S, et al. Characterization of the anticonvulsant activity and pharmacokinetics of propylisopropyl acetamide and its enantiomers. Br J Pharmacol 2003; 138: 602–613.PubMedCrossRefGoogle Scholar
  23. 23.
    Sobol E, Bialer M, Yagen B. Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives. J Med Chem 2004;47: 4316–4326.PubMedCrossRefGoogle Scholar
  24. 24.
    Winkler I, Sobol E, Yagen B, Steinman A, Devor M, Bialer M. Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model for neuropathic pain. Neuropharmacology 2005;49: 1110–1120.PubMedCrossRefGoogle Scholar
  25. 25.
    Morre M, Keane PE, Vemieres JC, Simiand J, Roncucci R. Valproate: recent findings and perspectives. Epilepsia 1984;25(suppl 1): S5-S9.PubMedCrossRefGoogle Scholar
  26. 26.
    Haj-Yehia A, Bialer M. Structure-pharmacokinetic relationships in a series of valpromide isomers with antiepileptic activity. Pharm Res 1989;6: 683–689.PubMedCrossRefGoogle Scholar
  27. 27.
    Haj-Yehia A, Bialer M. Structure-pharmacokinetic relationships in a series of fatty acid amide isomers that possess anticonvulsant activity. J Pharm Sci 1990;79: 719–724.PubMedCrossRefGoogle Scholar
  28. 28.
    Badir K, Haj-Yehia A, Vree TB, van der Kleijn E, Bialer M. Pharmacokinetics and anticonvulsant activity of three mon-esteric prodrugs of valproic acid. Pharm Res 1991;8: 750–753.PubMedCrossRefGoogle Scholar
  29. 29.
    Bialer M. Clinical pharmacology of valpromide. Clin Pharmacokinet 1991;20: 114–122.PubMedCrossRefGoogle Scholar
  30. 30.
    Isoherranen N, White HS, Klein B, et al. Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy. Pharm Res 2003;20: 1293–1301.PubMedCrossRefGoogle Scholar
  31. 31.
    Spiegelstein O, Yagen B, Levy RH, et al. Stereoselective pharmacokinetics and pharmacodynamics of propylisopropyl acetamide, a CNS-active chiral amide analog of valproic acid. Pharm Res 1999; 16: 1582–1588.PubMedCrossRefGoogle Scholar
  32. 32.
    Barel S, Yagen B, Schurig V, et al. Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and epileptic patients. Clin Pharmacol Ther 1997;61: 442–449.PubMedCrossRefGoogle Scholar
  33. 33.
    Winkler I, Blotnik S, Shimshoni J, Yagen B, Devor M, Bialer M. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model for neuropathic pain. Br J Pharmacol 2005;146: 198–208.PubMedCrossRefGoogle Scholar
  34. 34.
    Applebaum J, Gayduk J, Agam G, Bersudsky Y, Belmaker RH. Valnoctamide as valproate substitute with low teratogenic potential: double blind controlled clinical trial. Bipolar Disord 2005;7(suppl 2): 30. Scholar
  35. 35.
    Eadie MJ. Could valerian have been the first anticonvulsant? Epilepsia 2004;45: 1338–1343.PubMedCrossRefGoogle Scholar
  36. 36.
    Bialer M, Hadad S, Kadry B, et al. Pharmacokinetic analysis and antiepileptic activity of tetramethylcyclopropyl analogues of valpromide. Pharm Res 1995;13: 284–289.CrossRefGoogle Scholar
  37. 37.
    Isoherranen N, White HS, Finnell RH, et al. Anticonvulsant profile and teratogenicity of N-methyl-tetramethylcyclopropyl carboxamide: a new antiepileptic drug. Epilepsia 2002;43: 115–126.PubMedCrossRefGoogle Scholar
  38. 38.
    Sobol E, Yagen B, White HS, et al. Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonylurea, a novel second generation to valproic acid, antiepileptic drug. Neuropharmacology 2006;51: 933–946.PubMedCrossRefGoogle Scholar
  39. 39.
    Sobol E, Yagen B, Winkler I, Britzi M, Gibson D, Bialer M. Pharmacokinetics and metabolism of a new potent anticonvulsant agent 2,2,3,3-tetramethylcyclopropylcarbonylurea in rats. Drug Metab Dispos 2005;33: 1538–1546.PubMedCrossRefGoogle Scholar
  40. 40.
    Okada A, Onishi Y, Aoki K, et al. Teratology studies of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice. Birth Defect Res (Part B) 2006;77: 1–7.CrossRefGoogle Scholar
  41. 41.
    Shaltiel G, Shamir A, Shapiro J, et al. Valproate decreases inositol biosynthesis. Biol Psychiatry 2004;56: 868–874.PubMedCrossRefGoogle Scholar
  42. 42.
    Sobol E, Yagen B, White HS, et al. Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide. Epilepsy Res 2006 [Epub ahead of print].Google Scholar
  43. 43.
    Hadad S, Bialer M. Pharmacokinetic analysis and antiepileptic activity of N-valproyl derivatives of GABA and glycine. Pharm Res 1995;12: 905–910.PubMedCrossRefGoogle Scholar
  44. 44.
    Isoherranen N, Yagen B, Speigelstien O, et al. Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in mice. Br J Pharmacol 2003;139: 755–764.PubMedCrossRefGoogle Scholar
  45. 45.
    Isoherranen N, Woodhead JH, White HS, Bialer M. Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug. Epilepsia 2001;42: 831–836.PubMedCrossRefGoogle Scholar
  46. 46.
    Hovinga CA. Valrocemide. Curr Opin Investig Drugs 2004;5: 101–106.PubMedGoogle Scholar
  47. 47.
    Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the sixth Eilat conference on new antiepileptic drugs (EILAT VI). Epilepsy Res 2002;51: 31–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: a summary of the eighth Eilat conference on new antiepileptic drugs (EILAT VIII). Epilepsy Res (in press).Google Scholar
  49. 49.
    dePaulis T. ONO-2506. Curr Opin Investig Drugs 2003;4: 863–867.PubMedGoogle Scholar
  50. 50.
    Blaheta RA, Cintal J. Anti-tumor mechanism of valproate: a novel role of an old drug. Med Res Rev 2002;22: 491–511.CrossRefGoogle Scholar
  51. 51.
    Blaheta RA, Nau H, Michaelis M, Cintal J. Valproate and valproate-analogues: potent tools to fight against cancer. Curr Med Chem 2002;9: 1417–1433.PubMedGoogle Scholar
  52. 52.
    Eyal S, Yagen B, Shimshoni J, Bialer M. Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active VPA constitutional isomers and derivatives. Biochem Pharmacol 2005;69: 1501–1508.PubMedCrossRefGoogle Scholar
  53. 53.
    De Felice L, Tararelli C, Mascolo MG, et al. Histone deacetylase inhibitor valproic acid enhances cytokine-induced expansion of human hematopoietic stem cells. Cancer Res 2005;65: 1505–1513.PubMedCrossRefGoogle Scholar
  54. 54.
    Bug G, Ritter M, Wassmann B, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 2005;104: 2717–2725.PubMedCrossRefGoogle Scholar
  55. 55.
    Bug G, Gul H, Schwartz K, et al. Valproic acid stimulated proliferation and self-renewal of hematopoietic stem cells. Cancer Res 2005;65: 2537–2541.PubMedCrossRefGoogle Scholar
  56. 56.
    Deubzer H, Busche B, Ronndahl G, et al. Novel valproic acid derivatives with potent differentiation-inducing activity in myeloid leukemia cells. Leuk Res 2006;30: 1167–1175.PubMedCrossRefGoogle Scholar
  57. 57.
    Selby R, Nisbet-Brown E, Basran RK, Chang L, Olivieri NF. Valproic acid and augmentation of fetal hemoglobin in individuals with and without sickle cell disease. Blood 1997;90: 891–893.PubMedGoogle Scholar
  58. 58.
    Atweh GF, De Simone J, Sauntharajah Y, et al. Hemoglobinopathies. Hematology Am Soc Hematol Educ Program 2003;1: 14–39.Google Scholar
  59. 59.
    Brill J, Lee M, Zhao S, Fernald RD, Huguenard JR. Chronic valproic acid treatment triggers increased neuropeptide Y expression and signaling in rat nucleus reticularis thalami. J Neurosci 2006;26: 6813–6822.PubMedCrossRefGoogle Scholar
  60. 60.
    Sun QQ, Barban SC, Rince DA, Huegenard JR. Target-specific neuropeptide Y-ergic synaptic inhibition and its network consequences within the mammalian thalamus. J Neurosci 2003;23: 9639–9649.PubMedGoogle Scholar
  61. 61.
    Wilmore LJ. Divalproex and epilepsy. Psychopharmacol Bull 2003;37(suppl 2): 43–53.Google Scholar
  62. 62.
    Bialer M, Twyman RE, White HS. Correlation between anticonvulsant-ED50 values of antiepileptic drugs in mice and rats and their therapeutic doses and plasma levels. Epilepsy Behav 2004; 5: 866–872.PubMedCrossRefGoogle Scholar
  63. 63.
    Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation. J Biol Chem 2003;278: 27586–27592.PubMedCrossRefGoogle Scholar
  64. 64.
    Jeong MR, Hashimoto R, Senatorov V, et al. Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition. FEBS Lett 2003;542: 74–78.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2007

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Department of Pharmaceutics, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemEin KaremIsrael
  3. 3.David R. Bloom Centre for PharmacyThe Hebrew University of JerusalemIsrael

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