吡唑并[4,3 - ]嘧啶衍生物作为一种新型的缺氧诱导因子脯氨酰羟化酶结构域抑制剂用于治疗贫血
Pyrazolo[4,3-]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia.
作者信息
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
机构信息
Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aobaku, Yokohama 227-0033, Japan.
Department of Chemistry, Graduate School of Science, Osaka University, 1-1, Machikaneyama, Toyonaka 560-0043, Japan.
出版信息
ACS Med Chem Lett. 2020 Jun 4;11(7):1416-1420. doi: 10.1021/acsmedchemlett.0c00108. eCollection 2020 Jul 9.
Abstract
Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIFα subunit. Thieno[2,3-]pyrimidine identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo[4,3-]pyrimidine as the lead compound of orally bioavailable HIF-PHD inhibitors. Conversion of the benzyl moiety in gave pyrazolopyrimidine with high solubility and bioavailability, which increased hemoglobin levels in anemic model rats after repeated oral administration. It was shown that pyrazolo[4,3-]pyrimidine derivatives are promising therapeutic agents for renal anemia through the inhibition of HIF-PHD.
摘要
抑制缺氧诱导因子脯氨酰羟化酶结构域（HIF-PHD）可通过稳定HIFα亚基来促进促红细胞生成素（EPO）的产生。基于X射线晶体结构分析鉴定出的噻吩并[2,3-b]嘧啶经优化后，发现吡唑并[4,3-d]嘧啶作为口服生物可利用的HIF-PHD抑制剂的先导化合物。[具体化合物名称]中苄基部分的转化得到了具有高溶解度和生物利用度的吡唑并嘧啶[具体化合物名称]，在反复口服给药后可提高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有望成为治疗肾性贫血的药物。
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10
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