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Bioorg Med Chem. 2012 Apr 1;20(7):2435-43. doi: 10.1016/j.bmc.2012.01.037. Epub 2012 Feb 7.

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

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  • 1Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
22370337
[PubMed - indexed for MEDLINE]
PMCID:
PMC3303928
Free PMC Article
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