Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives.
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.
Chen
Hua-Sin
HS
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Kuo
Sheng-Chu
SC
Teng
Che-Ming
CM
Lee
Fang-Yu
FY
Wang
Jih-Pyang
JP
Lee
Yu-Chun
YC
Kuo
Chiung-Wen
CW
Huang
Ching-Che
CC
Wu
Chin-Chung
CC
Huang
Li-Jiau
LJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D019007:P-Selectin / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001565:Benzoates; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D000255:Adenosine Triphosphate