1. 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction
- Author
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Hannah E. Canning, Natalie A. Webster, Robert J. Skene, Andrew Paul Ayscough, Susanne Wright, Saleh Ahmed, Livermore David, Anthony Ivetac, Steven James Wilkens, Natasha Kinsella, David Harrison, Robert Downham, Barker Gregory, Alan G. Hendrick, Kerry Jenkins, and Richard J. Davenport
- Subjects
0301 basic medicine ,Denticity ,Stereochemistry ,Pyridines ,010402 general chemistry ,Crystallography, X-Ray ,01 natural sciences ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,chemistry.chemical_compound ,Residue (chemistry) ,Mice ,Dogs ,Drug Discovery ,Pyridine ,Side chain ,Animals ,Humans ,Enzyme Inhibitors ,chemistry.chemical_classification ,biology ,Active site ,Oxidoreductase inhibitor ,Triazoles ,0104 chemical sciences ,Mice, Inbred C57BL ,Molecular Docking Simulation ,Benzonitrile ,030104 developmental biology ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine - 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.
- Published
- 2017