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
文献类型：期刊论文
| 作者 | Li, Shiliang2; Xu, Hongling2; Cui, Shichao1; Wu, Fangshu2; Zhang, Youli2; Su, Mingbo1; Gong, Yinghui2; Qiu, Shaobing2; Jiao, Qian2; Qin, Chun2 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-07-28 |
| 卷号 | 59期号:14页码:6772-6790 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6600505 |
| 文献子类 | Article |
| 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. |
| WOS关键词 | IV INHIBITOR ; BIOLOGICAL EVALUATION ; ASYMMETRIC-SYNTHESIS ; MEDICINAL CHEMISTRY ; HYBRID APPROACH ; WEB SERVER ; EFFICIENT ; ELECTROSTATICS ; PHARMACOLOGY ; ASSOCIATION |
| 资助项目 | Fundamental Research Funds for the Central Universities[00000000] ; National Natural Science Foundation of China[81222046] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21372078] ; National Natural Science Foundation of China[81302697] ; National Key Research and Development Program[2016YFA0502304] ; National Key Research and Development Program[2016YFA0502300] ; National S&T Major Project of China[2013ZX09507004] ; Twelfth Five-Year National Science & Technology Support Program[2012BAI29B06] ; Shanghai Commision of Science and Technology[13ZR1410600] ; Shanghai Commision of Science and Technology[15DZ2291600] ; Innovation Program of Shanghai Municipal Education Commission[13SG32] ; Fok Ying Tung Education Foundation[141035] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000380730600013 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275948]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Zhenjiang; Li, Jingya; Li, Honglin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Shiliang,Xu, Hongling,Cui, Shichao,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(14):6772-6790. |
| APA | Li, Shiliang.,Xu, Hongling.,Cui, Shichao.,Wu, Fangshu.,Zhang, Youli.,...&Li, Honglin.(2016).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.JOURNAL OF MEDICINAL CHEMISTRY,59(14),6772-6790. |
| MLA | Li, Shiliang,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 59.14(2016):6772-6790. |
入库方式： OAI收割
来源：上海药物研究所
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