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

  • J Med Chem. 2017 Jul 13;60(13):5663-5672. doi: 10.1021/acs.jmedchem.7b00352.
Saleh Ahmed ,  Andrew Ayscough ,  Greg R Barker ,  Hannah E Canning ,  Richard Davenport ,  Robert Downham ,  David Harrison ,  Kerry Jenkins ,  Natasha Kinsella ,  David G Livermore ,  Susanne Wright ,  Anthony D Ivetac  1 ,  Robert Skene  1 ,  Steven J Wilkens  1 ,  Natalie A Webster ,  Alan G Hendrick
Affiliations
  • 1. Department of Computational Sciences and Crystallography, Takeda California Inc. , 10410 Science Center Dr., San Diego, California 92121, United States.
PMID: 28594552 DOI: 10.1021/acs.jmedchem.7b00352
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.

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