Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

Abstract

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. After the promising results from clinical trials of FG-2216 (FibroGen’s HIF-PHD inhibitor), many pharmaceutical companies recognized the potential of HIF-PHD inhibitor and started developing their own HIF-PHD inhibitors. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with the compound. By optimizing the pyrimidine substituents, we discovered compound 4, which improves the effectiveness of erythropoietin (EPO) release from Hep3B cells. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vivo activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its oral administration for 4 consecutive days.