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.