Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia

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 by improving cell permeability led to the discovery of JTZ-951 (compound), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound was selected as a clinical candidate.

Solvent‐ and Catalyst‐Free Aza‐Michael Addition of Imidazoles and Related Heterocycles

“…Th., colorless solid. Analytical data in accordance with literature . 1 H‐NMR (300 MHz, CDCl 3 ) δ = 6.86, 6.82 (s, 2H, Im 4,5 ), 4.08 (t, J = 6.8 Hz, 2H, N‐C H 2 CH 2 ‐COO), 2.61 (t, J = 6.8 Hz, 2H, N‐CH 2 C H 2 ‐COO), 2.37 (s, 3H, Me), 1.39 (s, 9H, C(CH 3 ) 3 ) ppm.…”

A Mass Balance Study of 14C‐Labeled JTZ‐951 (Enarodustat), a Novel Orally Available Erythropoiesis‐Stimulating Agent, in Patients With End‐Stage Renal Disease on Hemodialysis

“…Blood samples for quantitation of plasma JTZ-951 and metabolite (R)-M2 were collected at 0 hour (predose) and at 0.25, 0.5, 1, 1. 5,2,3,4,6,8,12,16,24,36,48,72,96, and 120 hours postdose. Blood samples for quantitation of plasma and whole-blood 14 C radioactivity were collected at the time points shown above (except at 0.25 and 3 hours), with additional collections at 144 and 168 hours postdose.…”

“…JTZ-951 (enarodustat; chemical name: 2-({[7-Hydroxy-5-(2-phenylethyl)- [1,2,4]triazolo [1,5-a]pyridin-8-yl]carbonyl}amino) acetic acid) is a newly identified, orally available HIF-PH inhibitor. 8 In human HEP3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, EPO mRNA levels, and EPO production. Nonclinical in vivo studies with JTZ-951 showed increases in hemoglobin concentrations without vascular endothelial growth factor-related effects on retinal permeability or tumor growth.…”

The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease

“…12 We hypothesized that HIF stabilizers might reverse the metabolism alterations in diabetic renal cortical tissue, considering that HIF, as an adaptive response to hypoxia, reduces metabolic flux in cells to repress oxygen consumption. Thus, utilizing transcriptome and metabolome analyses, we conducted a proof-of-concept study to comprehensively understand how enarodustat (JTZ-951), 13,14 an oral HIF stabilizer, affects renal metabolism alterations occurring in the early stages of DKD.…”