Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia.
Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia.
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JTZ-951 的发现：一种用于治疗肾性贫血的 HIF 脯氨酰羟化酶抑制剂。
DOI：
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发表时间：
2017
影响因子：
4.2
通讯作者：
H. Abe
中科院分区：
文献类型：
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作者：
Yosuke Ogoshi;T. Matsui;Ikuo Mitani;M. Yokota;M. Terashita;Dai Motoda;Kazuhito Ueyama;T. Hotta;Takashi Ito;Y. Hase;K. Fukui;Katsuya Deai;H. Yoshiuchi;Soichiro Ito;H. Abe
抑制缺氧诱导因子脯氨酰羟化酶（PHD）代表了发现下一代肾性贫血治疗的一个有前途的策略。我们确定了几个5，6-稠环系统作为PHD抑制剂的药效团分析的基础上的新的支架。特别地，三唑并吡啶衍生物显示出有效的PHD 2抑制活性。通过静电计算检查三唑并吡啶在效力方面的优势，表明与Tyr 310存在有利的π-π堆积相互作用。通过改善细胞渗透性来改善促红细胞生成素在细胞中和体内释放的功效的铅优化导致发现JTZ-951（化合物14），其在三唑吡啶基团上具有5-苯乙基取代基，其在大鼠中每日口服给药时增加血红蛋白水平。化合物14在口服给药后被迅速吸收，并在此后不久消失，这在安全性方面可能是有利的。选择化合物14作为临床候选物。
Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.
影响因子：
13.6
作者：
Babitt, Jodie L.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.