TY - JOUR
T1 - Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes
AU - Li, Shiliang
AU - Qin, Chun
AU - Cui, Shichao
AU - Xu, Hongling
AU - Wu, Fangshu
AU - Wang, Jiawei
AU - Su, Mingbo
AU - Fang, Xiaoyu
AU - Li, Dan
AU - Jiao, Qian
AU - Zhang, Ming
AU - Xia, Chunmei
AU - Zhu, Lili
AU - Wang, Rui
AU - Li, Jia
AU - Jiang, Hualiang
AU - Zhao, Zhenjiang
AU - Li, Jingya
AU - Li, Honglin
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 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 A1c level.
AB - 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 A1c level.
UR - https://www.scopus.com/pages/publications/85061925335
U2 - 10.1021/acs.jmedchem.8b01491
DO - 10.1021/acs.jmedchem.8b01491
M3 - 文章
C2 - 30694668
AN - SCOPUS:85061925335
SN - 0022-2623
VL - 62
SP - 2348
EP - 2361
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -
