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.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Benzoates/chemistry , Blood Platelets/drug effects , Blood Platelets/metabolism , Humans , Molecular Structure , P-Selectin/metabolism , Platelet Aggregation Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
To search for novel compounds with potent anti-angiogenic activity, a series of N(1)-(substituted benzyl)-3-(4-methylphenyl)-1H-indazoles (16, 18, 20, 22, 24, 26, 28, 30, 32) and N(2)-(substituted benzyl)-3-(4-methylphenyl)-2H-indazoles (17, 19, 21, 23, 25, 27, 29, 31, and 33) were synthesized. The structures of these regioisomers were established by IR, UV, and NMR spectral data. 3-(4-Methylphenyl)-1H-indazole (6) and the N(2)-substituted derivatives (17, 19, 21, 23, 25, 29, 31, 33) were evaluated for their anti-angiogenic activity. Most of them showed more prominent activity than ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3). Among these tested compounds, 2-(4-chlorobenzyl)-3-(4-methylphenyl)-2H-indazole (19), 2-(4-methylbenzyl)-3-(4-methylphenyl)-2H-indazole (25), and 2-(4-methoxybenzyl)-3-(4-methylphenyl)-2H-indazole (31) showed significant anti-angiogenic activity and are worthy of further investigation.
