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

被引：10

作者：

Goi, Takashi ^{[1
,2
]}

Nakajima, Tatsuo ^{[1
]}

Komatsu, Yoshiyuki ^{[1
]}

Kawata, Atsushi ^{[1
]}

Yamakoshi, Shuhei ^{[1
]}

Okada, Okimasa ^{[1
]}

Sugahara, Masakatsu ^{[1
]}

Umeda, Asami ^{[1
]}

Takada, Yoko ^{[1
]}

Murakami, Jun ^{[1
]}

Ohashi, Rikiya ^{[1
]}

Watanabe, Tomoko ^{[1
]}

Fukase, Koichi ^{[2
]}

机构：

[1] Mitsubishi Tanabe Pharma Corp, Sohyaku Innovat Res Div, Yokohama, Kanagawa 2270033, Japan

[2] Osaka Univ, Dept Chem, Grad Sch Sci, Toyonaka, Osaka 5600043, Japan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 07期

关键词：

renal anemia; hypoxia-inducible factor prolyl hydroxylase domain inhibitor; erythropoietin; pyrazolopyrimidine; solubility; KIDNEY; ERYTHROPOIETIN; DISCOVERY;

D O I：

10.1021/acsmedchemlett.0c00108

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIF alpha 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.

引用

收藏

页码：1416 / 1420

页数：5

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