ml0c00108_si_001.pdf (3.53 MB)
Pyrazolo[4,3‑d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia
journal contribution
posted on 2020-06-04, 12:33 authored by Takashi Goi, Tatsuo Nakajima, Yoshiyuki Komatsu, Atsushi Kawata, Shuhei Yamakoshi, Okimasa Okada, Masakatsu Sugahara, Asami Umeda, Yoko Takada, Jun Murakami, Rikiya Ohashi, Tomoko Watanabe, Koichi FukaseInhibition
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.