Abstract
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
MeSH terms
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Animals
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Crystallography, X-Ray
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Dogs
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Humans
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Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
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Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
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Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
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Madin Darby Canine Kidney Cells
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Mice
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Triazoles / chemistry*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
Substances
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1,2,4-triazolo(3,4-a)pyridine
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Enzyme Inhibitors
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Pyridines
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Triazoles
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Hypoxia-Inducible Factor-Proline Dioxygenases