In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures

Qing Jing, Huiying Li, Jianguo Fang, Linda J. Roman, Pavel Martásek, Thomas L. Poulos, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

In certain neurodegenerative diseases damaging levels of nitric oxide (NO) are produced by neuronal nitric oxide synthase (nNOS). It, therefore, is important to develop inhibitors selective for nNOS that do not interfere with other NOS isoforms, especially endothelial NOS (eNOS), which is critical for proper functioning of the cardiovascular system. While we have been successful in developing potent and isoform-selective inhibitors, such as lead compounds 1 and 2, the ease of synthesis and bioavailability have been problematic. Here we describe a new series of compounds including crystal structures of NOS-inhibitor complexes that integrate the advantages of easy synthesis and good biological properties compared to the lead compounds. These results provide the basis for additional structure-activity relationship (SAR) studies to guide further improvement of isozyme selective inhibitors.

Original languageEnglish (US)
Pages (from-to)5323-5331
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2013

Keywords

  • Aminopyridines
  • Inhibition
  • Neuronal nitric oxide synthase
  • Nitric oxide

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures'. Together they form a unique fingerprint.

  • Cite this