Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
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DOI：
10.1371/journal.pone.0132004
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Schofield CJ
中科院分区：
文献类型：
--
作者：
Chan MC;Atasoylu O;Hodson E;Tumber A;Leung IK;Chowdhury R;Gómez-Pérez V;Demetriades M;Rydzik AM;Holt-Martyn J;Tian YM;Bishop T;Claridge TD;Kawamura A;Pugh CW;Ratcliffe PJ;Schofield CJ
作为细胞适应限制动物中氧气可用性的一部分，大量基因的表达通过低氧诱导转录因子（HIF）的上调而被激活。通过抑制HIF系统的缺氧感受器，即HIF脯氨酰羟化酶（PHD），可以实现天然人缺氧反应的治疗性激活。在这里，我们报告的研究三环三唑含化合物作为有效的和选择性的PHD抑制剂，与2-酮戊二酸共底物竞争。一种化合物（IOX 4）在细胞和野生型小鼠中诱导HIFα，在脑组织中具有显著的诱导作用，这表明它可用于旨在验证HIF上调治疗脑疾病（包括中风）的研究。
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.
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影响因子：
8.4
作者：
Hopkinson RJ;Tumber A;Yapp C;Chowdhury R;Aik W;Che KH;Li XS;Kristensen JBL;King ONF;Chan MC;Yeoh KK;Choi H;Walport LJ;Thinnes CC;Bush JT;Lejeune C;Rydzik AM;Rose NR;Bagg EA;McDonough MA;Krojer T;Yue WW;Ng SS;Olsen L;Brennan PE;Oppermann U;Muller-Knapp S;Klose RJ;Ratcliffe PJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
5.3
作者：
Ferguson, James E., III;Wu, Yaxu;Patterson, Cam
通讯作者：
Patterson, Cam
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Coleman, Mathew L.;McDonough, Michael A.;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.