2. Academic Validation
  3. Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists

Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists

  • J Med Chem. 2023 Jun 22;66(12):7988-8010. doi: 10.1021/acs.jmedchem.3c00320.
Lili Chen 1 2,  Ying Yun 3,  Shimeng Guo 1,  Xiaoyan Wang 1 2,  Muya Xiong 1 2,  Tingting Zhao 4,  Tifei Xu 1,  Jianhua Shen 1,  Xin Xie 1,  Kai Wang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
PMID: 37286364 DOI: 10.1021/acs.jmedchem.3c00320
Abstract

Danuglipron is the most representative small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) and has received considerable attention due to positive results in the treatment of type 2 diabetes mellitus (T2DM) and obesity in clinical trials. However, hERG inhibition, lower activity than endogenous GLP-1, and a short action time represent limitations in terms of feasible application. In this study, we report a new class of 5,6-dihydro-1,2,4-triazine derivatives that serve to eliminate potential hERG inhibition caused by the piperidine ring of danuglipron. Applying systematic in vitro to in vivo screening, we have identified compound 42 as a highly potent and selective GLP-1R agonist, which delivers improved (7-fold) efficacy in stimulating cAMP accumulation compared with danuglipron and which exhibits acceptable drug-like properties. Furthermore, 42 significantly reduces glucose excursion and inhibits food intake of hGLP-1R Knock-In mice. These effects are longer-lasting than that shown by danuglipron, demonstrating feasibility in the treatment of T2DM and obesity.

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