2. Academic Validation
  3. Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives

Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives

  • Bioorg Med Chem. 2008 Feb 1;16(3):1262-78. doi: 10.1016/j.bmc.2007.10.070.
Hua-Sin Chen 1,  Sheng-Chu Kuo,  Che-Ming Teng,  Fang-Yu Lee,  Jih-Pyang Wang,  Yu-Chun Lee,  Chiung-Wen Kuo,  Ching-Che Huang,  Chin-Chung Wu,  Li-Jiau Huang
Affiliations

Affiliation

  • 1 Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
PMID: 17988878 DOI: 10.1016/j.bmc.2007.10.070
Abstract

Previously, ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was identified by us as the first non-peptide Protease-activated Receptor 4 (PAR4) antagonist. To continue on our development of novel anti-PAR4 agents, YD-3 was used as a lead compound and a series of its derivatives were synthesized and evaluated for their selective anti-PAR4 activity. Through structure-activity relationship (SAR) study, we identified the important functional groups contributing to anti-PAR4 activity, and these functional groups were kept intact during subsequent structural modification. Several new compounds with anti-PAR4 activity comparable to YD-3 were identified. Among them, ethyl 4-[1-(3-chlorobenzyl)-1H-indazol-3-yl]benzoate (33) showed the most potent inhibitory effect on PAR4-mediated platelet aggregation, ATP release, and P-selectin expression. On the Other hand, ethyl 4-(1-phenyl-1H-indazol-3-yl)benzoate (83) exhibited dual inhibitory effects on PAR4 and thromboxane formation from arachidonic acid. The above findings can be used as guidelines for development of novel antiplatelet drug candidates.

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