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.
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This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Center for Advancing Translational Sciences (UL1TR001998) grant.
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-23482-4.
Ding, Kai; Zhou, Ziyuan; Hou, Shurong; Yuan, Yaxia; Zhou, Shuo; Zheng, Xirong; Chen, Jianzhong; Loftin, Charles D.; Zheng, Fang; and Zhan, Chang-Guo, "Structure-Based Discovery of mPGES-1 Inhibitors Suitable for Preclinical Testing in Wild-Type Mice as a New Generation of Anti-Inflammatory Drugs" (2018). Molecular Modeling and Biopharmaceutical Center Faculty Publications. 14.