文献类型：期刊文献

英文题名：Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes

作者：Li, Shiliang[1];Xu, Hongling[1];Cui, Shichao[2];Wu, Fangshu[1];Zhang, Youli[1];Su, Mingbo[2];Gong, Yinghui[1];Qiu, Shaobing[1];Jiao, Qian[1];Qin, Chun[1];Shan, Jiwei[1];Zhang, Ming[1];Wang, Jiawei[1];Yin, Qiao[1];Xu, Minghao[1];Liu, Xiaofeng[1];Wang, Rui[1];Zhu, Lili[1];Li, Jia[2];Xu, Yufang[1];Jiang, Hualiang[2];Zhao, Zhenjiang[1];Li, Jingya[2];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2016

卷号：59

期号：14

起止页码：6772

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000380730600013)】；

基金：We thank the staff at Shanghai Synchrotron Radiation Facility for assistance with data collection. The research is supported in part by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (Grants 81222046, 81230076, 21372078, and 81302697) (H.L., H.J., Z.Z., and L.Z.), the National Key Research and Development Program (Grants 2016YFA0502304, 2016YFA0502300), the National S&T Major Project of China (Grant 2013ZX09507004), the Twelfth Five-Year National Science & Technology Support Program (Grant 2012BAI29B06) (H.L.), and Shanghai Commision of Science and Technology (Grants 13ZR1410600 and 15DZ2291600) (J.L.). H.L. is also sponsored by the Innovation Program of Shanghai Municipal Education Commission (Grant 13SG32) and Fok Ying Tung Education Foundation (Grant 141035).

语种：英文

摘要：Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 approximate to 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.