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Pyrazolo[4,3-d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-06-04 , 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
Affiliation  

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.

中文翻译:

吡唑并[4,3-d]嘧啶衍生物作为新型缺氧诱导因子脯氨酰羟化酶域抑制剂治疗贫血。

缺氧诱导因子脯氨酰羟化酶结构域(HIF-PHD)的抑制通过稳定HIFα亚基来促进促红细胞生成素(EPO)的产生。优化基于X射线晶体结构分析鉴定的Thieno [2,3- d ]嘧啶8,以发现吡唑并[4,3- d ]嘧啶13作为口服生物利用的HIF-PHD抑制剂的先导化合物。苄基部分在13中的转化产生具有高溶解度和生物利用度的吡唑并嘧啶19,其在反复口服后增加了贫血模型大鼠的血红蛋白水平。结果表明吡唑并[4,3- d]嘧啶衍生物通过抑制HIF-PHD是有希望的治疗肾性贫血的药物。
更新日期:2020-07-09
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