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Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia
- Source :
- ACS Medicinal Chemistry Letters. 8:1320-1325
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π–π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.
- Subjects :
- 0301 basic medicine
Chemistry
Organic Chemistry
030232 urology & nephrology
HIF prolyl-hydroxylase inhibitor
Pharmacology
Biochemistry
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Hypoxia-inducible factors
Oral administration
Erythropoietin
In vivo
Drug Discovery
medicine
Potency
Triazolopyridine
Pharmacophore
medicine.drug
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....da4368beded07f0bdc3c33801b91b038