2. Academic Validation
  3. Discovery of 2,3-Dihydro[1,4]dioxino[2,3- g]benzofuran Derivatives as Protease Activated Receptor 4 (PAR4) Antagonists with Potent Antiplatelet Aggregation Activity and Low Bleeding Tendency

Discovery of 2,3-Dihydro[1,4]dioxino[2,3- g]benzofuran Derivatives as Protease Activated Receptor 4 (PAR4) Antagonists with Potent Antiplatelet Aggregation Activity and Low Bleeding Tendency

  • J Med Chem. 2024 Apr 11;67(7):5502-5537. doi: 10.1021/acs.jmedchem.3c02099.
Panpan Chen 1 2,  Cai Chen 1,  Yizheng Zheng 3,  Fangjun Chen 1,  Zhaojun Liu 3,  Shenhong Ren 3,  Hangyu Song 1,  Tongdan Liu 3,  Zhipeng Lu 2,  Hongbin Sun 1 4,  Yi Kong 3,  Haoliang Yuan 1 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 3 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
PMID: 38552183 DOI: 10.1021/acs.jmedchem.3c02099
Abstract

Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.

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