Discovery of 3-(Arylamido)pyrazolopyridine HIF-2α Agonists and a Codrug Strategy with Prolyl Hydroxylase Inhibition for Synergistic Treatment of Renal Anemia

Activation of the hypoxia-inducible factor-2 (HIF-2) pathway represents a promising strategy for the treatment of renal anemia. Here, we identify compound <b>48</b> (<b>ZG-2686</b>), a 3-(benzamido)pyrazolopyridine derivative, as a novel and potent HIF-2α agonist (<i>E</i>_max = 375.7 ± 9.7%, EC₅₀ = 0.25 ± 0.05 μM). Molecular dynamics (MD) simulations provided detailed insights into the binding mode of <b>48</b> with the HIF-2α/β complex. In cellular assays, <b>48</b> synergistically enhanced HIF-2α-dependent <i>EPO</i> gene expression when combined with the clinically approved prolyl hydroxylase domain (PHD) inhibitor Vadadustat. To further exploit this synergy, we designed and synthesized the bifunctional codrug <b>50</b> (<b>ZG-2688</b>), linking <b>48</b> with Vadadustat. Notably, codrug <b>50</b> induced superior upregulation of EPO levels <i>in vivo</i> compared to coadministration of the two individual agents. Together, these findings demonstrate the first rationally designed codrug integrating an HIF-2α agonist and a PHD inhibitor, highlighting a new direction for the development of renal anemia therapies.