Pyrazolo[4,3- d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia

  • ACS Med Chem Lett. 2020 Jun 4;11(7):1416-1420. doi: 10.1021/acsmedchemlett.0c00108.
Takashi Goi  1  2 ,  Tatsuo Nakajima  1 ,  Yoshiyuki Komatsu  1 ,  Atsushi Kawata  1 ,  Shuhei Yamakoshi  1 ,  Okimasa Okada  1 ,  Masakatsu Sugahara  1 ,  Asami Umeda  1 ,  Yoko Takada  1 ,  Jun Murakami  1 ,  Rikiya Ohashi  1 ,  Tomoko Watanabe  1 ,  Koichi Fukase  2
Affiliations
  • 1. Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aobaku, Yokohama 227-0033, Japan.
  • 2. Department of Chemistry, Graduate School of Science, Osaka University, 1-1, Machikaneyama, Toyonaka 560-0043, Japan.
PMID: 32676148 DOI: 10.1021/acsmedchemlett.0c00108
Abstract

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.

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