title: Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent.
abstract: A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action.
authors.affiliation: State Key Laboratory of Natural Medicines, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Shan
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhang
authors.forename: Yaoqiu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Bo
authors.initials: B
authors.lastname: Jiao
authors.forename: Weiyi
authors.initials: W
authors.lastname: Zheng
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Qi
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Gong
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Fusheng
authors.initials: F
authors.lastname: Lv
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D000077144:Clopidogrel; D004351:Drug Resistance; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D013876:Thiophenes; C574646:methyl 2-(2-acetoxy-6,7-dihydrothieno(3,2-c)pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate; D000077144:Clopidogrel; D013988:Ticlopidine