Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors
文献类型：期刊论文
| 作者 | Wu, Deyan2; Jin, Fangfang2; Lu, Weiqiang2; Zhu, Jin2; Li, Cui2; Wang, Wei2; Tang, Yun2; Jiang, Hualiang1,2 ; Huang, Jin2; Liu, Guixia2
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| 刊名 | CHEMICAL BIOLOGY & DRUG DESIGN
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| 出版日期 | 2012-06 |
| 卷号 | 79期号:6页码:897-906 |
| 关键词 | dipeptidyl peptidase IV inhibitors molecular docking pharmacophore modeling synthesis |
| ISSN号 | 1747-0277 |
| DOI | 10.1111/j.1747-0285.2012.01365.x |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | DPP-4 INHIBITOR ; HIGHLY POTENT ; DISCOVERY |
| 资助项目 | National Natural Science Foundation of China[21002028] ; National Natural Science Foundation of China[20902022] ; National Natural Science Foundation of China[30973642] ; National S&T Major Project, China[2011ZX09102-005-02] ; 111 Project[B07023] ; Fundamental Research Funds for the Central Universities[00000000] ; Shanghai Municipal Education Commission[10ZZ41] ; Shanghai Committee of Science and Technology[11DZ2260600] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000303382300003 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278072]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Huang, Jin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Wu, Deyan,Jin, Fangfang,Lu, Weiqiang,et al. Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2012,79(6):897-906. |
| APA | Wu, Deyan.,Jin, Fangfang.,Lu, Weiqiang.,Zhu, Jin.,Li, Cui.,...&Li, Jian.(2012).Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors.CHEMICAL BIOLOGY & DRUG DESIGN,79(6),897-906. |
| MLA | Wu, Deyan,et al."Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors".CHEMICAL BIOLOGY & DRUG DESIGN 79.6(2012):897-906. |
入库方式： OAI收割
来源：上海药物研究所
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