PMID- 37286364
OWN - NLM
STAT- MEDLINE
DCOM- 20230623
LR  - 20230627
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 66
IP  - 12
DP  - 2023 Jun 22
TI  - Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious 
      Glucagon-Like Peptide-1 Receptor Agonists.
PG  - 7988-8010
LID - 10.1021/acs.jmedchem.3c00320 [doi]
AB  - 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.
FAU - Chen, Lili
AU  - Chen L
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      China.
FAU - Yun, Ying
AU  - Yun Y
AD  - School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced 
      Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
FAU - Guo, Shimeng
AU  - Guo S
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Wang, Xiaoyan
AU  - Wang X
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      China.
FAU - Xiong, Muya
AU  - Xiong M
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      China.
FAU - Zhao, Tingting
AU  - Zhao T
AD  - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 
      210046, China.
FAU - Xu, Tifei
AU  - Xu T
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Shen, Jianhua
AU  - Shen J
AUID- ORCID: 0000-0002-9273-3409
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Xie, Xin
AU  - Xie X
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Wang, Kai
AU  - Wang K
AUID- ORCID: 0000-0002-7597-549X
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230607
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 290-38-0 (1,2,4-triazine)
RN  - 0 (Hypoglycemic Agents)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Glucagon-Like Peptide-1 Receptor/agonists
MH  - Hypoglycemic Agents/pharmacology/therapeutic use
MH  - Obesity/drug therapy
EDAT- 2023/06/08 01:08
MHDA- 2023/06/23 06:42
CRDT- 2023/06/07 21:37
PHST- 2023/06/23 06:42 [medline]
PHST- 2023/06/08 01:08 [pubmed]
PHST- 2023/06/07 21:37 [entrez]
AID - 10.1021/acs.jmedchem.3c00320 [doi]
PST - ppublish
SO  - J Med Chem. 2023 Jun 22;66(12):7988-8010. doi: 10.1021/acs.jmedchem.3c00320. Epub 
      2023 Jun 7.