Pyrazolo[4,3‑d]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-d]­pyrimidine 8 identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo­[4,3-d]­pyrimidine...

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Published inACS medicinal chemistry letters Vol. 11; no. 7; pp. 1416 - 1420
Main Authors Goi, Takashi, Nakajima, Tatsuo, Komatsu, Yoshiyuki, Kawata, Atsushi, Yamakoshi, Shuhei, Okada, Okimasa, Sugahara, Masakatsu, Umeda, Asami, Takada, Yoko, Murakami, Jun, Ohashi, Rikiya, Watanabe, Tomoko, Fukase, Koichi
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.07.2020
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
solubility
renal anemia
hypoxia-inducible factor prolyl hydroxylase domain inhibitor
erythropoietin
pyrazolopyrimidine
KIDNEY
DISCOVERY
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.0c00108