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

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

  • J Med Chem. 2023 Jul 13;66(13):8545-8563. doi: 10.1021/acs.jmedchem.3c00231.
Yue Wu 1 2,  Linjian Zhang 1 2,  Zhuoli Sun 1 3,  Xusheng Qiu 4,  Yafen Chen 1 3,  Kaijun Su 1 2,  Le Yang 1 2,  Zhongqiu Du 4,  Ying Dong 1 2,  Fulai Yang 1 2,  Xiang Li 1 3,  Xiaojin Zhang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Orthopedics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
PMID: 37367818 DOI: 10.1021/acs.jmedchem.3c00231
Abstract

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.

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