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Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3.
Thromb Haemost. 2002 Jun; 87(6):1026-33.TH

Abstract

In the present study, the antiplatelet effect and its mechanism of a new synthetic compound YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] were examined. YD-3 inhibited the aggregation of washed human platelets caused by protease-activated receptor (PAR) 4 agonist peptide GYPGKF (IC50 = 0.13 +/- 0.02 microM), but had no or little effect on that by thrombin, PAR1 agonist peptide SFLLRN, collagen or U46619. YD-3 produced a parallel, rightward shift of the concentration-response curve for GYPGKF without decreasing of the maximum platelet aggregation, indicating a competitive antagonism. In contrast to human platelets, both thrombin- and GYPGKF-induced mouse platelet shape change and aggregation were completely inhibited by YD-3. YD-3 also selectively prevented GYPGKF-induced intracellular Ca2+ mobilization in human platelets. Furthermore, in the PAR1-desensitized human platelets, thrombin induced a relatively slow rise and decay of calcium mobilization that was significantly inhibited by YD-3. In addition, the synergistic effect of SFLLRN and GYPGKF on platelet activation was prevented by YD-3. YD-3 also inhibits both fMLP-stimulated neutrophil- and purified cathepsin G-induced platelet aggregation, which has been demonstrated to be PAR4-dependent. Taken together, our results suggest that YD-3 selectively inhibits PAR4-dependent platelet activation through blockade of PAR4. To the best of our knowledge, it is the first non-peptide PAR4 antagonist.

Authors+Show Affiliations

Graduate Institute of Natural Products, Kaohsiung Medical University, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12083482

Citation

Wu, Chin-Chung, et al. "Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation By YD-3." Thrombosis and Haemostasis, vol. 87, no. 6, 2002, pp. 1026-33.
Wu CC, Hwang TL, Liao CH, et al. Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3. Thromb Haemost. 2002;87(6):1026-33.
Wu, C. C., Hwang, T. L., Liao, C. H., Kuo, S. C., Lee, F. Y., Lee, C. Y., & Teng, C. M. (2002). Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3. Thrombosis and Haemostasis, 87(6), 1026-33.
Wu CC, et al. Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation By YD-3. Thromb Haemost. 2002;87(6):1026-33. PubMed PMID: 12083482.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3. AU - Wu,Chin-Chung, AU - Hwang,Tsong-Long, AU - Liao,Chang-Hui, AU - Kuo,Sheng-Chu, AU - Lee,Fang-Yu, AU - Lee,Chun-Yann, AU - Teng,Che-Ming, PY - 2002/6/27/pubmed PY - 2003/8/26/medline PY - 2002/6/27/entrez SP - 1026 EP - 33 JF - Thrombosis and haemostasis JO - Thromb Haemost VL - 87 IS - 6 N2 - In the present study, the antiplatelet effect and its mechanism of a new synthetic compound YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] were examined. YD-3 inhibited the aggregation of washed human platelets caused by protease-activated receptor (PAR) 4 agonist peptide GYPGKF (IC50 = 0.13 +/- 0.02 microM), but had no or little effect on that by thrombin, PAR1 agonist peptide SFLLRN, collagen or U46619. YD-3 produced a parallel, rightward shift of the concentration-response curve for GYPGKF without decreasing of the maximum platelet aggregation, indicating a competitive antagonism. In contrast to human platelets, both thrombin- and GYPGKF-induced mouse platelet shape change and aggregation were completely inhibited by YD-3. YD-3 also selectively prevented GYPGKF-induced intracellular Ca2+ mobilization in human platelets. Furthermore, in the PAR1-desensitized human platelets, thrombin induced a relatively slow rise and decay of calcium mobilization that was significantly inhibited by YD-3. In addition, the synergistic effect of SFLLRN and GYPGKF on platelet activation was prevented by YD-3. YD-3 also inhibits both fMLP-stimulated neutrophil- and purified cathepsin G-induced platelet aggregation, which has been demonstrated to be PAR4-dependent. Taken together, our results suggest that YD-3 selectively inhibits PAR4-dependent platelet activation through blockade of PAR4. To the best of our knowledge, it is the first non-peptide PAR4 antagonist. SN - 0340-6245 UR - https://www.unboundmedicine.com/medline/citation/12083482/Selective_inhibition_of_protease_activated_receptor_4_dependent_platelet_activation_by_YD_3_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=12083482.ui DB - PRIME DP - Unbound Medicine ER -