Journal of Medicinal Chemistry p. 3088 - 3106 (2019)
Update date:2022-08-15
Topics:
Kong, Deyu
Xue, Tao
Guo, Bin
Cheng, Jianjun
Liu, Shunyin
Wei, Jianhai
Lu, Zhengyu
Liu, Haoran
Gong, Guoqing
Lan, Tian
Hu, Wenhao
Yang, Yushe
P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.
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