Abstract
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
MeSH terms
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Animals
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Binding Sites / drug effects
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Celecoxib
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Cyclooxygenase 1 / metabolism
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Cyclooxygenase 2 Inhibitors / chemical synthesis*
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Cyclooxygenase 2 Inhibitors / pharmacology*
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Dogs
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Drug Design
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Humans
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Hydrogen Bonding
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In Vitro Techniques
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Indicators and Reagents
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Kinetics
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Models, Molecular
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Nitriles / chemistry*
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Nitriles / pharmacology*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology*
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Pyridines / chemistry*
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Pyridines / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / pharmacology
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Sulfones / chemistry*
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Sulfones / pharmacology*
Substances
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1-(5-methylsulfonyl)pyrid-2-yl
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1-(5-methylsulfonyl)pyrid-4-nitrile
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Cyclooxygenase 2 Inhibitors
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Indicators and Reagents
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Nitriles
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Pyrazoles
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Pyridines
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Sulfonamides
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Sulfones
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Cyclooxygenase 1
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Celecoxib