Inhibition
of hypoxia-inducible factor prolyl hydroxylase domain
(HIF-PHD) promotes erythropoietin (EPO) production by stabilizing
the HIFα subunit. Thieno[2,3-d]pyrimidine 8 identified based on X-ray crystal structure analysis was
optimized to lead to the discovery of pyrazolo[4,3-d]pyrimidine 13 as the lead compound of orally bioavailable
HIF-PHD inhibitors. Conversion of the benzyl moiety in 13 gave pyrazolopyrimidine 19 with high solubility and
bioavailability, which increased hemoglobin levels in anemic model
rats after repeated oral administration. It was shown that pyrazolo[4,3-d]pyrimidine derivatives are promising therapeutic agents
for renal anemia through the inhibition of HIF-PHD.