Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs.
Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs.
复制标题
DOI：
10.1038/s41598-018-23482-4
复制
发表时间：
2018-03-26
影响因子：
4.6
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Ding K;Zhou Z;Hou S;Yuan Y;Zhou S;Zheng X;Chen J;Loftin C;Zheng F;Zhan CG
人mPGES-1被认为是下一代抗炎药物的一个有前途的靶点，没有目前可用的抗炎药物的副作用，文献中已经报道了各种抑制剂。然而，所报道的人mPGES-1的有效抑制剂中没有一种显示也是小鼠或大鼠mPGES-1的有效抑制剂，这妨碍了将已建立的炎症相关疾病的小鼠/大鼠模型用于临床前研究。因此，尽管在设计和发现各种人mPGES-1抑制剂方面进行了大量努力，但mPGES-1作为下一代抗炎药物靶点的前景从未在使用mPGES-1抑制剂的任何野生型小鼠/大鼠模型中得到证实。在这里，我们报告发现一种新型的选择性mPGES-1抑制剂有效的人类和小鼠mPGES-1酶，通过基于结构的合理设计。基于使用野生型小鼠的体内研究，该先导化合物确实无毒，口服生物可利用，并且与目前可用的药物塞来昔布相比，在降低PGE 2（一种炎症标志物）水平方面更有效。这是首次在野生型小鼠中证明mPGES-1确实是下一代抗炎药物的有希望的靶点。
Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs, and various inhibitors have been reported in the literature. However, none of the reported potent inhibitors of human mPGES-1 has shown to be also a potent inhibitor of mouse or rat mPGES-1, which prevents using the well-established mouse/rat models of inflammation-related diseases for preclinical studies. Hence, despite of extensive efforts to design and discover various human mPGES-1 inhibitors, the promise of mPGES-1 as a target for the next generation of anti-inflammatory drugs has never been demonstrated in any wild-type mouse/rat model using an mPGES-1 inhibitor. Here we report discovery of a novel type of selective mPGES-1 inhibitors potent for both human and mouse mPGES-1 enzymes through structure-based rational design. Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE2 (an inflammatory marker) levels compared to the currently available drug celecoxib. This is the first demonstration in wild-type mice that mPGES-1 is truly a promising target for the next generation of anti-inflammatory drugs.
登录
查看更多内容
影响因子：
2.7
作者：
Giroux, Andre;Boulet, Louise;Friesen, Richard W.
通讯作者：
Friesen, Richard W.
影响因子：
5.8
作者：
Bruno, Annalisa;Di Francesco, Luigia;Patrignani, Paola
通讯作者：
Patrignani, Paola
影响因子：
7.3
作者：
Hieke, Martina;Greiner, Christine;Werz, Oliver
通讯作者：
Werz, Oliver
影响因子：
6.7
作者：
Chini, Maria Giovanna;De Simone, Rosa;Bifulco, Giuseppe
通讯作者：
Bifulco, Giuseppe
影响因子：
2.7
作者：
Ding K;Zhou Z;Zhou S;Yuan Y;Kim K;Zhang T;Zheng X;Zheng F;Zhan CG
通讯作者：
Zhan CG