Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors

Elizabeth A. Litzinger, Pavel Martásek, Linda J. Roman, Richard B. Silverman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Based on computer modeling of the active site of nitric oxide synthases (NOS), a series of 10 amidine compounds (9-18) was designed including potential inhibitors that involve the coordination of side-chain functional groups with the iron of the heme cofactor. The most potent and selective compound was the methylthio amidine analogue 9, which was more potent than l-nitroarginine with 185-fold selectivity for inhibition of neuronal NOS over endothelial NOS. It also exhibited time-dependent inhibition, but did not involve the mechanism previously proposed for other amidine inhibitors of NOS. None of the compounds, however, exhibited heme-binding characteristics according to absorption spectroscopy.

Original languageEnglish (US)
Pages (from-to)3185-3198
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number9
DOIs
StatePublished - May 1 2006

Fingerprint

Amidines
Heme
Nitric Oxide Synthase
Testing
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III
Nitroarginine
Absorption spectroscopy
Functional groups
Catalytic Domain
Spectrum Analysis
Iron

Keywords

  • Absorption difference spectra
  • Enzyme inactivation
  • Enzyme inhibition
  • Heme ligands
  • Heme-binders
  • Nitric oxide synthase
  • Nitric oxide synthase inhibition

ASJC Scopus subject areas

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

Cite this

Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors. / Litzinger, Elizabeth A.; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 9, 01.05.2006, p. 3185-3198.

Research output: Contribution to journalArticle

Litzinger, Elizabeth A. ; Martásek, Pavel ; Roman, Linda J. ; Silverman, Richard B. / Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 9. pp. 3185-3198.
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