Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes
文献类型：期刊论文
| 作者 | Li, Shiliang1; Qin, Chun1; Cui, Shichao2,3; Xu, Hongling1; Wu, Fangshu1; Wang, Jiawei1; Su, Mingbo2; Fang, Xiaoyu1; Li, Dan2; Jiao, Qian1 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-03-14 |
| 卷号 | 62期号:5页码:2348-2361 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b01491 |
| 通讯作者 | Zhao, Zhenjiang(zhjzhao@ecust.edu.cn) ; Li, Jingya(jyli@simm.ac.cn) ; Li, Honglin(hlli@ecust.edu.cn) |
| 英文摘要 | Poor medication adherence is one of the leading causes of suboptimal glycaemic control in approximately half of the patients with type 2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically needed for improving patients' compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors play an increasingly important role in the treatment of T2DM because of their favorable properties of weight neutrality and hypoglycemia avoidance. Herein, we report the successful discovery and scale-up synthesis of compound 5, a structurally novel, potent, and long-acting DPP-4 inhibitor for the once-weekly treatment of T2DM. Inhibitor 5 has fast-associating and slow-dissociating binding kinetics profiles as well as slow clearance rate and long terminal half-life pharmacokinetic properties. A single-dose oral administration of 5 (3 mg/kg) inhibited >80% of DPP-4 activity for more than 7 days in diabetic mice. The long-term antidiabetic efficacies of 5 (10 mg/kg, qw) were better than those of the once-weekly trelagliptin and omarigliptin, especially in decreasing the hemoglobin Alc level. |
| WOS关键词 | TARGET RESIDENCE TIME ; DIPEPTIDYL PEPTIDASE-4 INHIBITORS ; MOLECULAR-ORBITAL METHOD ; DPP-4 INHIBITORS ; HYBRID APPROACH ; BINDING ; TRELAGLIPTIN ; POTENT ; MECHANISMS ; MANAGEMENT |
| 资助项目 | National Key Research and Development Program[2016YFA0502304] ; National Natural Science Foundation of China[81825020] ; National Natural Science Foundation of China[81803437] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Chinese Academy of Sciences[XDA12040204] ; Fundamental Research Funds for the Central Universities ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[U1501501] ; Shanghai Sailing Program[18YF1405100] ; National Program for Special Supports of Eminent Professionals ; National Program for Support of Top-notch Young Professionals |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000461537000010 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/290345]  |
| 专题 | 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.East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Shiliang,Qin, Chun,Cui, Shichao,et al. Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(5):2348-2361. |
| APA | Li, Shiliang.,Qin, Chun.,Cui, Shichao.,Xu, Hongling.,Wu, Fangshu.,...&Li, Honglin.(2019).Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes.JOURNAL OF MEDICINAL CHEMISTRY,62(5),2348-2361. |
| MLA | Li, Shiliang,et al."Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes".JOURNAL OF MEDICINAL CHEMISTRY 62.5(2019):2348-2361. |
入库方式： OAI收割
来源：上海药物研究所
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