Lee Sunkyung, Song Jong-Hwan, Park Chul Min, Kim Jin-Seok, Jeong Ji-Hye, Cho Woo-Young, Lim Dong-Chul
Division of Drug Discovery Research, Korea Research Institute of Technology , 141 Gajeongno, Yuseong, Deajeon 305-600, Korea.
R&D Park, LG Life Sciences , 104-1 Munji-Dong, Yuseong, Deajeon 305-380, Korea.
ACS Med Chem Lett. 2013 Sep 10;4(11):1054-8. doi: 10.1021/ml400235c. eCollection 2013 Nov 14.
Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure-activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high potency and no significant cytotoxicity; however, the compounds were metabolically unstable in both human and rat liver microsomes. Current research efforts are focused on optimizing the compounds to improve metabolic stability and physicochemical properties as well as potency.
八氢茚被鉴定为蛋白酶激活受体1（PAR1）拮抗剂的一种新型骨架。在此，对2位（C2）进行了构效关系（SAR）研究。在PAR1放射性配体结合试验中，化合物14、19和23b的IC50值分别为1.3、8.6和2.7 nM，并且在富血小板血浆（PRP）聚集试验中，它们对血小板活化的抑制活性与沃拉帕沙相当。这一系列化合物显示出高效力且无明显细胞毒性；然而，这些化合物在人和大鼠肝微粒体中代谢不稳定。目前的研究工作集中在优化这些化合物，以提高代谢稳定性、理化性质以及效力。
