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 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.

Figure 1

(a) Crystal structure of PHD2 in complex with FG-2216 and a representative pharmacophore common to typical PHD inhibitors (PDB code 2HBT). (b) Two binding models I and II of compound 4 bound to the active site of PHD2. (c) Electrostatic potential map of 5,6-fused ring systems. Positive, negative, and neutral charges are colored in blue, red, and white, respectively. The pyridine moiety is outlined by the green box.

Figure 2

Changes in hemoglobin levels following 29-day once-daily dosing of 7 (magenta) and 14 (green) in rats. Standard deviations are reported in the Supporting Information.

Figure 3

(a) Pharmacokinetic curves of 14 in rats. Each data point represents the mean ± SD (n = 3). (b) PK parameters of 14 in rats. (c) PK related parameters of 14.

Scheme 1. Synthesis of 14

Reagents and conditions: (a) tert-butyl 2,2,2-trichloroacetimidate, BF₃·Et₂O, THF; (b) benzyl alcohol, NaH, DMF, 0 °C; (c) hydrazine hydrate, 1,4-dioxane, 100 °C; (d) p-TsOH·H₂O, trimethyl orthoformate, 60 °C; (e) morpholine, AcOEt, reflux; (f) I₂, LHMDS, THF, −60 °C; (g) phenylacetylene, PdCl₂(PPh₃)₂, CuI, TEA, toluene; (h) MsOH, toluene–AcOEt; (i) glycine ethyl ester hydrochloride, EDC, HOBt, TEA, DMF; (j) H₂, Pd–C, THF–MeOH; (k) 4 N NaOH aq., EtOH, reflux.