Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase

Huiying Li, Fengtian Xue, James M. Kraus, Haitao Ji, Kristin Jansen Labby, Jan Mataka, Silvia L. Delker, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors.

Original languageEnglish (US)
Pages (from-to)1333-1343
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number5
DOIs
StatePublished - Mar 1 2013

Keywords

  • Cyclopropyl analogues
  • Inhibition
  • Isozyme selectivity
  • Neuronal nitric oxide synthase
  • X-ray crystallography

ASJC Scopus subject areas

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

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  • Cite this

    Li, H., Xue, F., Kraus, J. M., Ji, H., Labby, K. J., Mataka, J., Delker, S. L., Martásek, P., Roman, L. J., Poulos, T. L., & Silverman, R. B. (2013). Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. Bioorganic and Medicinal Chemistry, 21(5), 1333-1343. https://doi.org/10.1016/j.bmc.2012.12.019