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

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-2 alpha agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, E-max = 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-2 alpha agonists and the treatment of renal anemia.

Automated summary

A novel HIF-2 alpha agonist, compound 26, was discovered with potent nanomolar activity and the ability to enhance HIF-2 dimerization. It showed good pharmacokinetic and in vivo safety profiles, and when combined with the prolyl hydroxylase inhibitor AKB-6548, it synergistically increased plasma erythropoietin levels in mice and alleviated zebrafish anemia induced by doxorubicin. These findings suggest potential therapeutic implications for HIF-2 alpha agonists in the treatment of renal anemia.