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ID: ALA4014353
Journal: J Med Chem
Title: 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.
Authors: Ahmed S, Ayscough A, Barker GR, Canning HE, Davenport R, Downham R, Harrison D, Jenkins K, Kinsella N, Livermore DG, Wright S, Ivetac AD, Skene R, Wilkens SJ, Webster NA, Hendrick AG.
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.
CiteXplore: 28594552