Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid

Journal of Medicinal Chemistry

Volumn 50, Issue 25, 2007, Pages 6419-6427

  Shimshoni, Jakob Avi ^a   Bialer, Meir ^a   Wlodarczyk, Bogdan ^b   Finnell, Richard H ^b   Yagen, Boris ^a,c  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

^b TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

^c HEBREW UNIVERSITY OF JERUSALEM   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

2 ETHYL 3 METHYL PENTANOYLUREA; 2 ETHYL 3 METHYLPENTANOYL UREA; 2 ISOPROPYL 3 METHYLBUTANOYL UREA; 2 ISOPROPYLPENTANOIC ACID; 2 ISOPROPYLPENTANOYL UREA; 2 ISOPROPYLVALERAMIDE; 2 PROPYLPENTANOYL UREA; ANTICONVULSIVE AGENT; DIISOPROPYLACETAMIDE; DIISOPROPYLACETIC ACID; DIISOPROPYLACETYLUREA; OCTANOYLUREA; PROPYLISOPROPYLACETIC ACID; PROPYLISOPROPYLACETYLUREA; UNCLASSIFIED DRUG; UREA DERIVATIVE; VALNOCTAMIDE; VALNOCTIC ACID; VALPROIC ACID;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICONVULSANT ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG SYNTHESIS; ENANTIOMER; ENANTIOSELECTIVITY; ISOMERISM; LETHAL DOSE; MOUSE; NEURAL TUBE DEFECT; NEUROTOXICITY; NONHUMAN; RAT; SEIZURE; TERATOGENICITY;

ABNORMALITIES, DRUG-INDUCED; ANIMALS; ANTICONVULSANTS; EPILEPSY, COMPLEX PARTIAL; MICE; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; UREA; VALPROIC ACID;

EID: 37049031057     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm7009233     Document Type: Article

References (59)

1. McNamara, J. O. Pharmacotherapy of the Epilepsies. In The Pharmacological Basis of Therapeutics, 11th ed.; Brunton, L. L., Lazo, J. S., Parker, K. L., Eds.; McGraw-Hill, New York, 2006; pp 501-525.
2. Bourgeois, F. D. B. Valproic Acid: Clinical Efficacy and Use in Epilepsy. In Antiepileptic Drugs, 5th ed.; Levy, R. H., Mattson, R. H., Meldrum, B. S., Perucca, E., Eds.; Lippincott Williams & Wilkins Publishers, New York, 2002; pp 808-817.
3. Koenig, S. A.; Buesing, D.; Longin, E.; Oehring, R.; Häussermann, P.; Kluger, G.; Lindmayer, F.; Hanusch, R.; Degen, I.; Kuhn, H.; Samii, K.; Jungck, A.; Brückner, R.; Seitz, R.; Boxtermann, W.; Weber, Y.; Knapp, R.; Richard, H. H.; Weidner, B.; Kasper, J. M.; Haensch, C. A.; Fitzek, S.; Hartmann, M.; Borusiak, P.; Müller-Deile, A.; Degenhardt, V.; Korenke, G. C.; Hoppen, T.; Specht, U.; Gerstner, T. Valproic Acid-Induced Hepatopathy: Nine New Fatalities in Germany from 1994 to 2003. Epilepsia 2006, 47, 2027-2031.
4. Tomson, T.; Battino, D. Teratogenicity of Antiepileptic Drugs: State of the Art. Curr. Opin. Neurol. 2005, 18, 135-140.
5. Vajda, F. J.; O'Brien, T. J.; Hitchcock, A.; Graham, J.; Cook, M.; Lander, C.; Eadie, M. J. Critical Relationship between Sodium Valproate Dose and Human Teratogenicity: Results of the Australian Register of Anti-Epileptic Drugs in Pregnancy. J. Clin. Neurol. 2004, 11, 854-858.
6. Sussman, N. M.; McLean, L. W., Jr. A Direct Hepatotoxic Effect of Valproic Acid. JAMA. 1979, 242, 1173-1174.
7. Zimmerman, H. J.; Ishak, K. G. Valproate-Induced Hepatic Injury: Analysis of 23 Fatal Cases. Hepatology 1982, 2, 591-597.
8. Nau, H.; Loscher, W. Pharmacological Evaluation of Various Metabolites and Analogous of Valproic Acid: Teratogenic Potencies in Mice. Fundam. Appl. Toxicol. 1986, 6, 669-676.
9. 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.
10. Hauck, R. S.; Nau, H.; Elmazar, M. M. On the Development of Alternative Antiepileptic Drugs. Lack of Enantioselectivity of the Anticonvulsant Activity, in Contrast to Teratogenicity, of 2-n-propyl-4-pentenoic Acid and 2-n-propyl-4-pentynoic Acid, Analogues of the Anticonvulsant Drug Valproic Acid. Naturwissenschaften 1991, 78, 272-274.
11. Isoherranen, N.; Yagen, B.; Bialer, M. New CNS-Active Drugs Which Are Second-Generation Valproic Acid: Can They Lead to the Development of a Magic Bullet. Curr. Opin. Neurol. 2003, 16, 203-211.
12. Loscher, W.; Nau, H. Pharmacological Evaluation of Various Metabolites and Analogues of Valproic Acid. Neuropharmacolgy. 1985, 24, 427-435.
13. Liu, M. J.; Pollack, G. M. Pharmacokinetics and Pharmacodynamics of Valproate Analogues in Rats: IV. Antiepileptic Action and Neurotoxicity of Octanoic Acid, Cyclohexanecarboxylic Acid, and 1-Methyl-1-Cyclohexanecarboxylic Acid. Epilepsia 1994, 35, 234-243.
14. Morre, M.; Keane, P. E.; Vernieres, J. C.; Simiand, J.; Roncucci, R. Valproate: Recent Findings and Perspectives. Epilepsia 1984, 25 (Suppl. 1), S5-S9.
15. Keane, P. E.; Simiand, J.; Mendes, E.; Santucci, V.; Morre, M. The Effects of Analogues of Valproic Acid on Seizures Induced by Pentylenetetrazole and GABA Content in Brain of Mice. Neuropharmacology 1983, 22, 875-879.
16. Bojic, U.; Elmazar, M. M. A.; Hauck, R. S.; Nau, H. Further Branching of Valproate-Related Carboxylic Acids Reduces the Teratogenic Activity, but not the Anticonvulsant Effect. Chem. Res. Toxicol. 1996, 9, 866-870.
17. Abbott, S. F.; Acheampong, A. A. Quantitative Structure-Anticonvulsant Activity Relationships of Valproic Acid, Related Carboxylic Acids and Tetrazoles. Neuropharmacology 1988, 27, 287-294.
18. Badir, K.; Haj-Yehia, A.; Vree, B. T.; Van Der Kleijn, E.; Bialer, M. Pharmacokinetics and Anticonvulsant Activity of Three Monoesteric Prodrugs of Valproic Acid. Pharm. Res. 1991, 8, 750-753.
19. Haj-Yehia, A.; Bialer, M. Structure-Pharmacokinetic Relationships in a Series of Valpromide Derivatives with Antiepileptic Activity. Pharm. Res. 1989, 6, 683-689.
20. Haj-Yehia, A.; Bialer, M. Structure-Pharmacokinetic Relationships in a Series of Short Fatty Acid Amides that Possess Anticonvulsant Activity. J. Pharm. Sci. 1990, 79, 719-724.
21. Redecker, C.; Altrup, U.; Hoppe, D.; Dusing, R.; Speckmann, E.-J. Effects of Valproate Derivatives I. Antiepileptic Efficacy of Amides, Structural Analogues and Esters. Neuropharmacology 2000, 39, 254-266.
22. Bialer, M. Clinical Pharmacology of Valpromide. Clin. Pharmacokinet. 1991, 20, 114-122.
23. Hadad, S.; Bialer, M. Pharmacokinetic Analysis and Antiepileptic Activity of N-Valproyl Derivatives of GABA and Glycine. Pharm. Res. 1995, 12, 905-910.
24. Isoherranen, N.; Yagen, B.; Woodhead, J. H.; Spiegelstein, O.; Blotnik, S.; Wilcox, S. K.; Finnell, R. H.; Bennett, D. G.; White, S. H.; Bialer, M. Characterization of the Anticonvulsant Profile and Enantioselective Pharmacokinetics of the Chiral Valproylamide Propylisopropyl Acetamide in Rodents. Br. J. Pharmacol. 2003, 138, 602-613.
25. Isoherranen, N.; White, S. H.; Klein, B. D.; Roeder, M.; Woodhead, J. H.; Schuring, V.; Yagen, B.; Bialer, M. Pharmacokinetic-Pharmacodynamic Relationship of (2S, 3S)-Valnoctamide and its Stereoisomer (2R, 3S)-Valnoctamide in Rodent Models of Epilepsy. Pharm. Res. 2003, 20, 1293-1301.
26. Spiegelstein, O.; Yagen, B.; Levy, R. H.; Finnell, R. H.; Bennett, G. D.; Roeder, M.; Schuring, V.; Bialer, M. Stereoselective Pharmacokinetics and Pharmacodynamics of Propylisopropylacetamide, a CNS-Active Chiral Amide Analog of Valproic Acid. Pharm. Res. 1999, 16, 1582-1588.
27. Davidou, P. The Spectrum of Action of Valnoctamide in Daily Psychiatric Practice. Toulouse Med. 1964, 65, 1127-1158.
28. Applebaum, J.; Gayduk, J.; Agam, G.; Bersudsky, Y.; Belmaker, R. H. Valnoctamide as Valproate Substitute with Low Teratogenic Potential: Double Blind Controlled Clinical Trial. Bipolar Disorder 2005, 7 (Suppl. 2), 30 http//www.clinicaltrials.gov/ct/show/NCT00140179.
29. Barel, S.; Yagen, B.; Schurig, V.; Soback, S.; Pisani, F.; Perucca, E.; Bialer, M. Stereoselective Pharmacokinetic Analysis of Valnoctamide in Healthy Subjects and in Patients with Epilepsy. Clin. Pharmacol. Ther. 1997, 61, 442-449.
30. Levi, M.; Yagen, B.; Bialer, M. Pharmacokinetics and Antiepileptic Activity of Valproyl Hydroxamic Acid Derivatives. Pharm. Res. 1997, 14, 213-217.
31. Hadad, S.; Bialer, M. Pharmacokinetic Analysis and Antiepileptic Activity of Two New Isomers of N-Valproyl Glycinamide. Biopharm. Drug Disposit. 1997, 18, 557-566.
32. Isoherranen, N.; Woodhead, H. J.; White, H. S.; Bialer, M. Anticonvulsant Profile of Valrocemide (TV1901): A New Antiepileptic Drug. Epilepsia 2001, 42, 831-836.
33. Bialer, M.; Johannessen, S. I.; Kupferberg, H. J.; Levy, R. H.; 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. 2007, 73, 1-52.
34. Spielman, M. A.; Geiszler, A. O.; Close, W. J. Anticonvulsant Drugs, IL Some Acetyureas. J. Am. Chem. Soc. 1948, 70, 4189-4191.
35. Tantisira, B.; Tantisira, M. H.; Patarapanich, C.; Sooksawate, T.; Chunngam, T. Preliminary Evaluation of Anticonvulsant Activity of a Valproic Acid Analogue: N-(2-propylpentanoyl)urea. Res. Commun. Mol. Pathol. Pharmacol. 1997, 97, 151-164.
36. Winkler, I.; Sobol, E.; Yagen, B.; Steinmman, A.; Devor, M; Bialer, M. Efficacy of Antiepileptic Tetramethylcyclopropyl Analogues of Valproic Acid Amides in a Rat Model of Neuropathic Pain. Neuropharmacology 2005, 49, 1110-1120.
37. 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.
38. Sobol, E.; Yagen, B.; White, H. S.; Wilcox, K. S.; Lamb, J. G.; Pappo, O.; Wlodarczyk, B. J.; Finnell, R. H.; Bialer, M. Preclinical Evaluation of 2,2,3,3-Tetramethylcyclopropanecarbonylurea, a Novel, Second Generation to Valproic Acid, Antiepileptic Drug. Neuropharmacology 2006, 51, 933-946.
39. Isoherranen, N.; White, H. S.; Finnell, R. H.; Yagen, B.; Woodhead, J. H.; Bennett, G. D.; Wilcox, K. S.; Barton, M. E.; Bialer, M. Anticonvulsant Profile and Teratogenicity of N-Methyl-Tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug. Epilepsia 2002, 43, 115-126.
40. Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M., Jr. α Anions of Carboxylic Acids. II. The Formation and Alkylation of α-Metalated Aliphatic Acids. J. Org. Chem. 1972, 37, 451-458.
41. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's Textbook of Practical Organic Chemistry; Prentice Hall: New York, 1989; pp 720-723.
42. Spiegelstein, O.; Bialer, M.; Radatz, M.; Nau, H.; Yagen, B. Enantioselective Synthesis and Teratogenicity of Propylisopropyl Acetamide, a CNS-Active Chiral Amide Analogue of Valproic Acid. Chirality 1999, 11, 645-650.
43. Katz, J.; Finestone, S. C.; Peppas, M. T.; Fine, J. A Double-Blind Evaluation of Capuride (Pacinox®) as Presurgical Aid to Sleep. Curr. Ther. Res. 1970, 12, 255-260.
44. Goldstein, L; Pfeiffer, C. C. Quantitative EEG Analysis of Single-Dose Effect Relationships in Normal Volunteers of Pacinox (Capuride), a New Antianxiety Drug. Biol. Pyschiatry 1971, 3, 165-171.
45. Johnson, P. C.; Cressman, W. A.; Driscoll, B. S. Absorption and Excretion of a Monoureide Hypnotic, Capuride. Clin. Phrmacol. Ther. 1972, 13, 377-379.
46. Kudo, K.; Kiyoshima, A.; Ohtsuka, Y.; Ikeda, N. Simultaneous Determination of Bromvalerylurea and Allylisopropylacetylurea in Human Blood and Urine by Gas Chromatography-Mass Spectrometry. J. Chromatogr., B: Biomed. Sci. Appl. 2003, 791, 171-177.
47. Loscher, W.; Honack, D. Profile of UCB L059, a Novel Anticonvulsant Drug, in Models of Partial and Generalized Epilepsy in Mice and Rats. Eur. J. Pharmacol. 1993, 232, 147-158.
48. Barton, M. E.; Kleijn, B. D.; Wolf, H. H.; White, H. S. Pharmacological Characterization of the 6 Hz Psychomotor Seizure Model of Partial Epilepsy. Epilepsy Res. 2001, 47, 217-227.
49. White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf, H. H. Discovery and Preclinical Development of Antiepileptic Drugs. In Antiepileptic Drugs, 5th ed.; Levy, R. H., Mattson, R. H., Meldrum, B. S., Perucca, E., Eds.; Lippincott Williams & Wilkins Publishers: New York, 2002; pp 36-48.
50. Smith, M.; Wilcox, K. S.; White, H. S. Discovery of Antiepileptic Drugs. Neurotherapeutics 2007, 4, 12-17.
51. Levy, R. H.; Boddy, A. V. Stereoselectivity in Pharmacokinetics: A General Theory. Pharm. Res. 1991, 8, 551-556.
52. Janz, R.; Goda, Y.; Geppert, M.; Missler, M.; Sudhof, T. C. SV2A and SV2B Function as Redundant Ca2+ Regulators in Neurotransmitter Release. Neuron 1999, 24, 1003-1016.
53. Radatz, M.; Ehlers, K.; Yagen, B.; Bialer, M.; Nau, H. Valnoctamide, Valpromide and Valnoctic Acid are Much Less Teratogenic in Mice than Valproic Acid. Epilepsy Res. 1998, 30, 41-48.
54. Bojic, U.; Ehlers, K.; Ellerbeck, U.; Bacon, C. L.; O'Driscoll, E.; O'Connell, C.; Berezin, V.; Kawa, A.; Lepekhin, E.; Bock, E.; Regan, C. M.; Nau, H. Studies on the Teratogen Pharmacophore of Valproic Acid Analogues: Evidence of Interactions at a Hydrophobic Center. Eur. J. Phrmacol. 1998, 354, 289-299.
55. Wu, C. Y.; Benet, L. Z. Predicting Drug Disposition via Application on BCS: Transpoit/Absorption/Elimintaion Interplay and Development of a Biopharmaceutics Drug Disposition Classification System. Pharm. Res. 2005, 22, 11-23.
56. Finney, D. J. Probit Analysis, 3rd ed.; Cambridge University Press: Cambridge U.K., 1971.
57. Finnell, R. H.; Bennett, G. D.; Karras, S. B.; Mohl, V. K. Common Hierarchies of Susceptibility to the Induction of Neural Tube Defects by Valproic Acid and its 4-Propyl-4-Pentenoic Acid Metabolite. Teratology 1988, 38, 313-320.
58. Wlodarczyk, B. C.; Craig, J. C.; Bennett, G. D.; Calvin, J. A.; Finnell, R. H. Valproic Acid-Induced Changes in Gene Expression During Neurulation in a Mouse Model. Teratology 1996, 45, 284-297.
59. Bialer, M. Pharmacokinetic Considerations in the Design of Better and Safer New Antiepileptic Drugs. J. Controlled Release 1999, 62, 187-19.