The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase

Jan Pićha, Václav Vaňek, Miloš Budě̌́sińsky, Jana Mlad́ková, Timothy A. Garrow, Jiř́i Jiŕ̌acek

Research output: Contribution to journalArticle

Abstract

Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the "homocysteine" part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the "homocysteine" part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely defi ne the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine.

Original languageEnglish (US)
Pages (from-to)256-275
Number of pages20
JournalEuropean Journal of Medicinal Chemistry
Volume65
DOIs
StatePublished - Jan 1 2013

Keywords

  • Amino acid derivative
  • BHMT
  • Bioisostere
  • Homocysteine
  • Inhibitor
  • Phosphinate
  • Phosphonate
  • S-alkylated homocysteine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Pićha, J., Vaňek, V., Budě̌́sińsky, M., Mlad́ková, J., Garrow, T. A., & Jiŕ̌acek, J. (2013). The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase. European Journal of Medicinal Chemistry, 65, 256-275. https://doi.org/10.1016/j.ejmech.2013.04.039