- 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors with a Novel Monodentate Binding Interaction
-
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.
- Ahmed, Saleh,Ayscough, Andrew,Barker, Greg R.,Canning, Hannah E.,Davenport, Richard,Downham, Robert,Harrison, David,Jenkins, Kerry,Kinsella, Natasha,Livermore, David G.,Wright, Susanne,Ivetac, Anthony D.,Skene, Robert,Wilkens, Steven J.,Webster, Natalie A.,Hendrick, Alan G.
-
supporting information
p. 5663 - 5672
(2017/07/22)
-
- New method for the general synthesis of [1,2,4]triazolo[1,5-a]pyridines
-
[1,2,4]Triazolo[1,5-a]pyridines without substituants on the 2-position have been prepared from 2-aminopyridines by cyclization of N-(pyrid-2-yl) formamidoximes with trifluoroacetic anhydride. Triazoles substituted at any position on the pyridine ring may be prepared in good yields and under mild reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Huntsman, Elliott,Balsells, Jaume
-
p. 3761 - 3765
(2007/10/03)
-