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

Abstract

Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative <b>26</b> was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC₅₀ = 490 nM, <i>E</i>_max = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that <b>26</b> could allosterically enhance HIF-2 dimerization. Furthermore, compound <b>26</b> had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an <i>in vivo</i> safety profile (the LD₅₀ in mice was greater than 708 mg·kg^-1). In the <i>in vivo</i> efficacy assays, the combination of <b>26</b> and the prolyl hydroxylase inhibitor, <b>AKB-6548</b>, 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.