Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors

Erik P. Erdal, Pavel Martásek, Linda J. Roman, Richard B. Silverman

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells. Whereas creating a lower level of NO in some cells could be beneficial, it also could be detrimental to the protective effects that NO has on other cells. Therefore, it is essential that therapeutic NOS inhibitors be made that are subtype selective. Previously, we reported a series of nitroarginine-containing dipeptide amides as potent and selective nNOS inhibitors. Here we synthesize peptidomimetic hydroxyethylene isosteres of these dipeptide amides for potential increased bioavailability. None of the compounds is as potent or selective as the dipeptide amides, but they exhibit good inhibition and selectivity. When the terminal amino group was converted to a hydroxyl group, potency and selectivity greatly diminished, supporting the importance of the terminal amino group for binding.

Original languageEnglish (US)
Pages (from-to)6096-6108
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number18
DOIs
StatePublished - Sep 15 2007

Keywords

  • Enzyme inhibitor
  • Hydroxyethylene isostere
  • Nitric oxide
  • Nitric oxide synthase
  • nNOS inhibitor

ASJC Scopus subject areas

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

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