Pharmacokinetic Analysis of the Structural Requirements for Forming “Stable” Analogues of Valpromide

Abdulla Haj-Yehia, Salim Hadad, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be “stable” to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the β position of its chemical structure. A “stable” valpromide analogue must have either two substitutions at the β position, such as in the case of TBD, or a substitution in the α and β positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.

Original languageEnglish
Pages (from-to)1058-1063
Number of pages6
JournalPharmaceutical Research
Volume9
Issue number8
DOIs
StatePublished - Aug 1992

Keywords

  • pharmacokinetics
  • stable analogues
  • structural requirements
  • valpromide

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