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Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.

Abstract
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.
AuthorsParamita Mukherjee, Huiying Li, Irina Sevrioukova, Georges Chreifi, Pavel Martásek, Linda J Roman, Thomas L Poulos, Richard B Silverman
JournalJournal of medicinal chemistry (J Med Chem) Vol. 58 Issue 3 Pg. 1067-88 (Feb 12 2015) ISSN: 1520-4804 [Electronic] United States
PMID25489882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Pyrimidines
  • Nitric Oxide Synthase Type I
Topics
  • Animals
  • Cell Membrane Permeability (drug effects)
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nitric Oxide Synthase Type I (antagonists & inhibitors, metabolism)
  • Pyrimidines (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Structure-Activity Relationship

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