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.

Synthesis and biological activities of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives as PDE4 inhibitors.

A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.