1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction.
J Med Chem
; 60(13): 5663-5672, 2017 07 13.
Article
en En
| MEDLINE
| ID: mdl-28594552
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Piridinas
/
Triazoles
/
Inhibidores Enzimáticos
/
Prolina Dioxigenasas del Factor Inducible por Hipoxia
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2017
Tipo del documento:
Article