New substrates and inhibitors of γ-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: Design, synthesis, and biological activity

Hai Yuan, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

A series of potential substrates of γ-aminobutyric acid aminotransferase (GABA-AT) with lipophilic bioisosteres of the carboxylic acid group (2-7) were synthesized and tested. Most of the synthesized compounds showed substrate activities with GABA-AT; 1H-tetrazole-5-propanamine (6) was the best of those tested. The potential time-dependent inhibitor of GABA-AT, 1H-tetrazole-5-(α-vinyl-propanamine) (8), was designed based on the structures of 6 and the antiepilepsy drug vigabatrin (4-aminohex-5-enoic acid, 1). The synthesized compound 8 showed time-dependent inhibition of GABA-AT, but its potency is lower than that of vigabatrin. Methylation of the tetrazole group in 8 resulted in loss of time-dependent activity, suggesting that the tetrazole ring, the carboxylate bioisostere, exists in its deprotonated form in the enzyme active site.

Original languageEnglish (US)
Pages (from-to)1331-1338
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number5
DOIs
StatePublished - Mar 1 2006

Keywords

  • Bioisostere
  • GABA-AT
  • Tetrazole
  • Vigabatrin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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