Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia.

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

Tetrahydropyridin-4-ylpicolinoylglycines as novel and orally active prolyl hydroxylase 2 (PHD2) inhibitors for the treatment of renal anemia.

Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the degradation of hypoxia-inducible factor-α (HIF-α). Pharmacological inhibition of PHD2 stabilizes HIF-α and induces the production of endogenous erythropoietin (EPO), which is regarded as a promising strategy for the treatment of renal anemia. To date, a series of PHD2 inhibitors have been approved or advanced into clinical studies. In this study, we developed a new type of PHD2 inhibitors with the tetrahydropyridin-4-ylpicolinoylglycine scaffold by using a scaffold hopping strategy. Among them, compound 25 showed potent inhibition toward PHD2 with an IC50 of 6.55 ± 0.41 nM. Furthermore, compound 25 upregulated reticulocytes in C57BL/6 mice. The subacute toxicological assay demonstrated 25 has no obvious toxicity in vivo. Overall, compound 25 is a promising candidate for the treatment of renal anemia.