Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia

  • J Med Chem. 2021 Dec 9;64(23):17384-17402. doi: 10.1021/acs.jmedchem.1c01479.
Yancheng Yu  1  2 ,  Fulai Yang  2 ,  Quanwei Yu  1  2 ,  Simeng Liu  1  2 ,  Chenyang Wu  1  2 ,  Kaijun Su  1  2 ,  Le Yang  1  2 ,  Xiaoqian Bao  1  2 ,  Zhihong Li  1  2 ,  Xiang Li  2  3 ,  Xiaojin Zhang  1  2
Affiliations
  • 1. Sate Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Laboratory of Drug Design and Discovery, Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China.
PMID: 34709043 DOI: 10.1021/acs.jmedchem.1c01479
Abstract

Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.

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