title: Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives.
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.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors.forename: Hua-Sin
authors.initials: HS
authors.lastname: Chen
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Lee
authors.forename: Jih-Pyang
authors.initials: JP
authors.lastname: Wang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lee
authors.forename: Chiung-Wen
authors.initials: CW
authors.lastname: Kuo
authors.forename: Ching-Che
authors.initials: CC
authors.lastname: Huang
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
mesh_terms: 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
chemical_list: D001565:Benzoates; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D000255:Adenosine Triphosphate