Synthesis of cyclopropane isosteres of the antiepilepsy drug vigabatrin and evaluation of their inhibition of GABA aminotransferase

Zhiyong Wang, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; γ-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5′-phosphate (PLP)-dependent enzyme γ-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M. and Silverman, R. B. (1991) J. Am. Chem. Soc. 113, 9341-9349), a Michael addition pathway (Scheme 2, pathway a) and an enamine pathway (Scheme 2, pathway b). Analogs of vigabatrin with a cyclopropyl or cyanocyclopropyl functionality in place of the vinyl group (2-5) were synthesized as potential inactivators of GABA-AT that can inactivate the enzyme only through a Michael addition pathway, but they were found to be only weak inhibitors of the enzyme.

Original languageEnglish (US)
Pages (from-to)293-301
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume19
Issue number4
DOIs
StatePublished - Jan 1 2004

Keywords

  • GABA
  • GABA-AT
  • Vigabatrin
  • γ-Aminobutyric acid
  • γ-Aminobutyric acid aminotransferase

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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