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

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.
AuthorsKristin Jansen Labby, Fengtian Xue, James M Kraus, Haitao Ji, Jan Mataka, Huiying Li, Pavel Martásek, Linda J Roman, Thomas L Poulos, Richard B Silverman
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 7 Pg. 2435-43 (Apr 01 2012) ISSN: 1464-3391 [Electronic] England
PMID22370337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Nitric Oxide Synthase Type I
Topics
  • Binding Sites
  • Catalytic Domain
  • Cell Membrane Permeability (drug effects)
  • Crystallography, X-Ray
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy
  • Nitric Oxide Synthase Type I (antagonists & inhibitors, metabolism)

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