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

  • J Med Chem. 2019 Mar 14;62(5):2348-2361. doi: 10.1021/acs.jmedchem.8b01491.
Shiliang Li  1 ,  Chun Qin  1 ,  Shichao Cui  2  3 ,  Hongling Xu  1 ,  Fangshu Wu  1 ,  Jiawei Wang  1 ,  Mingbo Su  2 ,  Xiaoyu Fang  1 ,  Dan Li  2 ,  Qian Jiao  1 ,  Ming Zhang  1 ,  Chunmei Xia  2 ,  Lili Zhu  1 ,  Rui Wang  1 ,  Jia Li  2 ,  Hualiang Jiang  2 ,  Zhenjiang Zhao  1 ,  Jingya Li  2  3 ,  Honglin Li  1
Affiliations
  • 1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy , East China University of Science and Technology , Shanghai 200237 , China.
  • 2. State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • 3. University of Chinese Academy of Sciences , No. 19A Yuquan Road , Beijing 100049 , P. R. China.
PMID: 30694668 DOI: 10.1021/acs.jmedchem.8b01491
Abstract

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.

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