2. Academic Validation
  3. Optimization of P2Y12 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

Optimization of P2Y12 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

  • J Med Chem. 2019 Mar 28;62(6):3088-3106. doi: 10.1021/acs.jmedchem.8b01971.
Deyu Kong 1 2,  Tao Xue 2,  Bin Guo 2,  Jianjun Cheng 3,  Shunyin Liu 1,  Jianhai Wei 1,  Zhengyu Lu 2,  Haoran Liu 2,  Guoqing Gong 4,  Tian Lan 4,  Wenhao Hu 1 5,  Yushe Yang 2
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering , East China Normal University , Shanghai 200062 , P. R. China.
  • 2 State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , P. R. China.
  • 3 iHuman Institute , ShanghaiTech University , Shanghai 201210 , P. R. China.
  • 4 Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , Jiangsu Province 210009 , P. R. China.
  • 5 School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , P. R. China.
PMID: 30843696 DOI: 10.1021/acs.jmedchem.8b01971
Abstract

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.

Figures
Products