Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.

Original languageEnglish (US)
Pages (from-to)2435-2443
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2012

Keywords

  • Enzyme inhibitors
  • Intramolecular hydrogen bond
  • Neuronal nitric oxide synthase

ASJC Scopus subject areas

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

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