文献类型：期刊文献

英文题名：Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes

作者：Li, Shiliang[1];Qin, Chun[1];Cui, Shichao[2,3];Xu, Hongling[1];Wu, Fangshu[1];Wang, Jiawei[1];Su, Mingbo[2];Fang, Xiaoyu[1];Li, Dan[2];Jiao, Qian[1];Zhang, Ming[1];Xia, Chunmei[2];Zhu, Lili[1];Wang, Rui[1];Li, Jia[2];Jiang, Hualiang[2];Zhao, Zhenjiang[1];Li, Jingya[2,3];Li, Honglin[1]

机构：[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

年份：2019

卷号：62

期号：5

起止页码：2348

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000461537000010)】；

基金：This work was supported by the National Key Research and Development Program [2016YFA0502304 to H.L.]; the National Natural Science Foundation of China (grant 81825020 to H.L., 81803437 to S.L.); the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (number: 2018ZX09711002); the Chinese Academy of Sciences (XDA12040204), the Fundamental Research Funds for the Central Universities, Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under grant no. U1501501. S.L. is sponsored by the Shanghai Sailing Program (no. 18YF1405100). H.L. is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

语种：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.