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

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

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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