期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 238, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114479
关键词
PHD2 inhibitor; HIF; Renal anemia
资金
- National Natural Science Foundation of China [81973173]
- Jiangsu Province Funds for Distinguished Young Scientists [BK20211527]
- Six Talent Peaks Project [YY-023]
This study developed a novel type of PHD2 inhibitor, with compound 25 showing potent inhibition of PHD2 in vivo and no obvious toxicity, making it a promising candidate for the treatment of renal anemia.
Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the degradation of hypoxia-inducible factor-alpha (HIF-alpha). Pharmacological inhibition of PHD2 stabilizes HIF-alpha 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.
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