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1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.

Saleh AhmedAndrew AyscoughGreg R BarkerHannah E CanningRichard DavenportRobert DownhamDavid HarrisonKerry JenkinsNatasha KinsellaDavid G LivermoreSusanne WrightAnthony D IvetacRobert SkeneSteven J WilkensNatalie A WebsterAlan G Hendrick
Published in: Journal of medicinal chemistry (2017)
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.
Keyphrases
  • magnetic resonance imaging
  • high resolution
  • dna binding
  • endothelial cells
  • magnetic resonance
  • computed tomography
  • molecular dynamics
  • transcription factor
  • binding protein
  • contrast enhanced