文献类型：期刊文献

英文题名：Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors

作者：Wu, Deyan[1];Jin, Fangfang[1];Lu, Weiqiang[1];Zhu, Jin[1];Li, Cui[1];Wang, Wei[1];Tang, Yun[1];Jiang, Hualiang[1,2];Huang, Jin[1];Liu, Guixia[1];Li, Jian[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

年份：2012

卷号：79

期号：6

起止页码：897

外文期刊名：CHEMICAL BIOLOGY & DRUG DESIGN

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000303382300003)】；

基金：We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (Grants 21002028, 20902022 and 30973642), National S&T Major Project, China (Grant 2011ZX09102-005-02), the 111 Project (Grant B07023), the Fundamental Research Funds for the Central Universities, the Innovation Program of Shanghai Municipal Education Commission (Grant 10ZZ41), and the Shanghai Committee of Science and Technology (Grant 11DZ2260600).

语种：英文

外文关键词：dipeptidyl peptidase IV; inhibitors; molecular docking; pharmacophore modeling; synthesis

摘要：Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (15) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6kl, and 7ae) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structureactivity relationships. Based on eight DPP-4 inhibitors (15, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.