Pharmaceutical Research

, Volume 6, Issue 8, pp 683–689

Structure–Pharmacokinetic Relationships in a Series of Valpromide Derivatives with Antiepileptic Activity

  • Abdulla Haj-Yehia
  • Meir Bialer

DOI: 10.1023/A:1015934321764

Cite this article as:
Haj-Yehia, A. & Bialer, M. Pharm Res (1989) 6: 683. doi:10.1023/A:1015934321764


The following valpromide (VPD) derivatives were synthesized and their structure–pharmacokinetic relationships explored: ethylbutylacetamide (EBD), methylpentylacetamide (MPD), propylisopropylacetamide (PID), and propylallylacetamide (PAD). In addition, the anticonvulsant activity of these compounds was evaluated and compared to that of VPD, valnoctamide (VCD), and valproic acid (VPA). MPD, the least-branched compound had the largest clearance and shortest half-life of all the amides investigated and was the least active. All other amides had similar pharmacokinetic parameters. Unlike the other amides, PID and VCD did not metabolize to their respective homologous acids and were the most active compounds. Our study showed that these amides need an unsubstituted β position in their aliphatic side chain in order to biotransform to their homologous acids. An amide which is not metabolized is more potent as an anticonvulsant than its biotransformed isomer. All amides were more active than their respective homologous acids. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the anticonvulsant activity was affected by the pharmacokinetics in general and by the biotransformation of the amide to its homologous acid in particular. This amide–acid biotransformation appeared to be dependent upon the chemical structure, especially upon the substitution at position β of the molecule.

valpromidevalproic acidantiepileptic activitySARpharmacokinetics

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Abdulla Haj-Yehia
    • 1
  • Meir Bialer
    • 1
  1. 1.Department of Pharmacy, School of PharmacyHebrew University of JerusalemJerusalemIsrael