Open AccessPyrazolo[4,3-d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia
Author(s) -
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 Fukase
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00108
Subject(s) - pyrimidine , hypoxia inducible factors , bioavailability , erythropoietin , chemistry , pyrimidine metabolism , pharmacology , pharmacokinetics , moiety , anemia , hypoxia (environmental) , stereochemistry , biochemistry , enzyme , medicine , gene , oxygen , organic chemistry , purine
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.