Imidazole-containing amino acids as selective inhibitors of nitric oxide synthases

Younghee Lee, Pavel Martasek, Linda J. Roman, Bettie Sue Siler Masters, Richard B. Silverman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Two series of imidazole-containing amino acids (1a-e and 2a-c), all larger homologues and analogues of L-histidine, were prepared. Since imidazole and phenyl substituted imidazoles have been reported to be inhibitors of NOS and the mode of action of these compounds as heme ligands is a potential mechanism of inhibitory action, we designed imidazole-containing amino acids as combined inhibitors at both the amino acid as well as heme binding sites. To study the influence of the distance between the amino acid moiety and the imidazole moiety on inhibitory potency, the number of carbons between these two functional groups was varied from two to six. The structure-activity relationships of this class of inhibitors can be correlated with the distance between the heme and the amino acid binding sites of the enzyme. Two of the compounds (1b and 1d) with three and five methylenes between the imidazole and amino acid functional groups, respectively, were found to be potent and selective inhibitors for nNOS and iNOS over eNOS. When phenyl was substituted on the nitrogen of the imidazole, both the potency and isoform selectivity diminished.

Original languageEnglish (US)
Pages (from-to)1941-1951
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number9
DOIs
StatePublished - Sep 1 1999

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Keywords

  • Histidine analogues
  • Imidazole-containing amino acids
  • Inhibitors
  • Nitric oxide synthase

ASJC Scopus subject areas

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

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