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

• Published in: European journal of medicinal chemistry 2022-08, Vol.238, p.114479, Article 114479
• Main Authors: Su, Kaijun, Li, Zhihong, Zhang, Linjian, Fang, Shaocong, Mao, Mingxuan, Sun, Zhuoli, Zhang, Xiaojin
• Format: Article
• Language: English
• Subjects: Anemia - drug therapy; Anemia - metabolism; Animals; HIF; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Mice; Mice, Inbred C57BL; PHD2 inhibitor; Procollagen-Proline Dioxygenase - metabolism; Prolyl-Hydroxylase Inhibitors - pharmacology; Pyridines - pharmacology; Renal anemia
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114479

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. [Display omitted] •Novel PHD2 inhibitors with tetrahydropyridin-4-ylpicolinoylglycine scaffold.•Detailed SAR study by a fluorescence polarization-based assay.•Compounds 21–25 showed potent in vitro inhibition towards PHD2.•Compound 25 is a candidate for renal anemia with good efficacy in C57BL/6 mouse.