Click Chemistry-Based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia-Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia

Abstract

As a gene associated with anemia, the erythropoiesis gene is physiologically expressed under hypoxia regulated by †hypoxia-inducing factor-α (HIF-α). Thus, stabilizing HIF-α is a potent strategy to stimulate the expression and secretion of erythropoiesis. In this study, we applied click chemistry to the discovery of HIF prolyl hydroxylase 2 (HIF-PHD2) inhibitors for the first time, and a series of triazole compounds showed preferable inhibitory activity in fluorescence polarization assays. Of particular note was the orally active HIF-PHD inhibitor 15i (IC = 62.23 nM), which was almost ten times more active than the phase III drug FG-4592 (IC = 591.4 nM). Furthermore, it can upregulate the hemoglobin of cisplatin-induced anemia mice (120 g/L) to normal levels (160 g/L) with no apparent toxicity observed in vivo. These results confirm that triazole compound 15i is a promising candidate for the treatment of renal anemia.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…Wu et al 151 suggested that the triazole compound 124 (Fig. 17) is a highly potent candidate for the treatment of renal anaemia.…”

Small-Molecule Modulators of the Hypoxia-Inducible Factor Pathway: Development and Therapeutic Applications

“…Notably, the orally active inhibitor 83 has an IC 50 of 62.3 nM, as determined by an FP assay, which is almost 10 times more potent in vitro than the recently approved drug FG-4592. 133 Compound 83 can stabilize HIF-α to stimulate EPO formation, thereby up-regulating hemoglobin to normal levels in cisplatin-induced anemic mice; this was associated with favorable safety profiles for treating anemia. 133 Further, Merck recently used a high throughput screen method to report on a novel class of PHD pan inhibitors with promising pharmacokinetics and pharmacodynamics.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-3

“…Today, inhibiting hypoxia-inducing factor prolyl hydroxylase 2 (HIF-PHD2) by an orally active small molecule is regarded as an effective strategy to stabilize HIF-α and then improve endogenous EPO level for anemia treatment. Recently, Wu et al [ 21 ] reported the details of a study to screen, optimize, and identify triazole compounds as potent HIF-PHD2 inhibitors based on click chemistry. Of particular note was the orally active HIF-PHD2 inhibitor N -(5-(1-(3-(4-chlorophenyl)propyl)-1 H -1,2,3-triazol-4-yl)-3-hydroxypicolinoyl)glycine (IC 50 = 62 nM), which was almost ten times more active than the phase III drug FG-4592 (IC 50 = 591 nM).…”