Discovery and synthesis of a novel series of quinoline-based thrombin receptor (PAR-1) antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 6; pp. 1544 - 1548
• Main Authors: Clasby, Martin C., Chackalamannil, Samuel, Czarniecki, Michael, Doller, Dario, Eagen, Keith, Greenlee, William J., Lin, Yan, Tsai, Hsingan, Xia, Yan, Ahn, Ho-Sam, Agans-Fantuzzi, Jacqueline, Boykow, George, Chintala, Madhu, Foster, Carolyn, Bryant, Matthew, Lau, Janice
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2006; Elsevier
• Subjects: Animals; Antagonist; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Macaca fascicularis; Medical sciences; PAR-1; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Quinoline; Quinolines - chemistry; Receptor; Receptor, PAR-1 - antagonists & inhibitors; Receptors, Thrombin - metabolism; Structure-Activity Relationship; Thrombin; Quinoline; Thrombin; PAR-1; Antagonist; Receptor; Monkey; Quinoline derivatives; Acetic acid derivative; In vitro; PAR1 protease-activated receptor; Vertebrata; Mammalia; Ex vivo; Structure activity relation; Animal; Primates; Affinity; Chemical synthesis; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.12.042

The synthesis and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC50=6.3nM), a related compound 36 showing efficacy in a monkey ex vivo study.