Optimization of P2Y 12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties

P2Y antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyri...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-03, Vol.62 (6), p.3088-3106
Main Authors: Kong, Deyu, Xue, Tao, Guo, Bin, Cheng, Jianjun, Liu, Shunyin, Wei, Jianhai, Lu, Zhengyu, Liu, Haoran, Gong, Guoqing, Lan, Tian, Hu, Wenhao, Yang, Yushe
Format: Article
Language:English
Subjects:
Animals
Drug Discovery
Humans
Male
Niacin - analogs & derivatives
Niacin - chemistry
Niacin - pharmacokinetics
Niacin - pharmacology
Platelet Aggregation Inhibitors - chemistry
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Aggregation Inhibitors - pharmacology
Purinergic P2Y Receptor Antagonists - chemistry
Purinergic P2Y Receptor Antagonists - pharmacokinetics
Purinergic P2Y Receptor Antagonists - pharmacology
Rats
Rats, Sprague-Dawley
Rats, Wistar
Receptors, Purinergic P2Y12 - drug effects
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
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Summary:P2Y antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01971