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 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC 50 = 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 LD 50 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.

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

“…Developed by Akebia, Cambridge, Boston, United States, vadadustat, an orally administered HIF-PHI based on a hydroxypyridine core and a carbonylglycine side chain, inhibits PHD3 more than the other two PHDs and stabilizes HIF-2α to a greater extent than HIF-1α ( Maynard et al, 2003 ; Yu Y. et al, 2021 ). Studies published currently have proved an anemia-alleviating effect of vadadustat in CKD patients undergoing dialysis and non-dialysis with ESA-untreated or ESA-treated ( Chertow et al, 2021 ; Eckardt et al, 2021 ; Nangaku et al, 2021c ; Nangaku et al, 2021d ).…”

CuBr2-Catalyzed Annulation of 2-Bromo-N-Arylbenzimidamide with Se/S8 Powder for the Synthesis of Benzo[d]isoselenazole and Benzo[d]isothiazole

“…N- benzo [d]isothiazol -3-amine (3r). 24 White solid (46.5 mg, 76% yield); petroleum ether/ethyl acetate = 10/1 as an eluent. 1 H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.85 (d,J = 8.1 Hz,1H),7.76 (d,J = 8.1 Hz,1H),7.62 (d,J = 7.8 Hz,1H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.23−7.12 (m, 2H), 7.03 (s, 1H).…”

“…0, 152.1, 136.4, 135.4, 134.0, 129.2, 127.9, 126.2, 123.9, 121.3, 120.4, 21.0, 18.4 N- (3,benzo [d]isothiazol-3-amine (3z). 24 (CAS: 2685739-28-8) Light yellow oil (23.8 3,154.1,150.9,142.0,128.1,127.1,124.2,120.7,120.4,96.5,94.6,isothiazol-3-amine (3aa). 16 Light yellow solid (36.8 mg, 76% yield); petroleum ether/ethyl acetate = 20/1 as an eluent.…”

“…N- benzo [d]isothiazol -3-amine (3o). 24 Light yellow solid (41.0 mg, 80% yield); petroleum ether/ethyl acetate = 10/1 as an eluent. 1 H NMR (400 MHz, chloroform-d) δ 7.84 (d,J = 8.1 Hz,1H),7.78 (d,J = 8.1 Hz,1H), 7.57 (s, 1H), 7.52 (t, J = 7.…”

Scaffold hopping strategy to derive 4‐hydroxy‐1‐alkyl‐2‐oxo‐1,2‐dihydrothieno[2,3‐b:4,5‐b′]dipyridine‐3‐carbonylglycine derivatives as a novel hypoxia‐inducible factor prolyl hydroxylase domain inhibitor for the potential treatment of chronic kidney disease anemia

“…ongoing. [12][13][14][15] To develop a novel PHD inhibitor, we adopted a scaffold hopping strategy using known PHD inhibitors. Based on a common glycine motif among the known PHD inhibitors, including roxadustat, vadadustat, daprodustat, and molidustat, we envisioned that a carbonylglycine moiety is essential for exhibiting inhibitory activity against PHD2.…”