Pyrazolo[4,3-]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia.

Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIFα subunit. Thieno[2,3-]pyrimidine identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo[4,3-]pyrimidine as the lead compound of orally bioavailable HIF-PHD inhibitors. Conversion of the benzyl moiety in gave pyrazolopyrimidine with high solubility and bioavailability, which increased hemoglobin levels in anemic model rats after repeated oral administration. It was shown that pyrazolo[4,3-]pyrimidine derivatives are promising therapeutic agents for renal anemia through the inhibition of HIF-PHD.