Lead Optimization to Advance Protease-Activated Receptor‑1 Antagonists in Early Discovery

• Published in: Journal of medicinal chemistry 2022-04, Vol.65 (7), p.5575-5592
• Main Authors: Mandal, Mihirbaran, Madeira, Maria, Amin, Rupesh P, Buevich, Alexei V, Cheng, Alan, Labroli, Marc, Liu, Xiaoxiang, Acton, John, Pio, Barbara, Basso, Andrea, Chobanian, Harry, Dong, Grace, Dropinski, Jamie, Guo, Yan, Guo, Zhuyan, Kurowski, Stan, Korfmacher, Walter, Lee, Sandra, Meng, Dongfang, Ondeyka, Debra, Yang, Zhiqiang, Zhang, Rumin, Wei, Huijun, Wu, Zhicai, Zhang, Fengqi, Wollenberg, Gordon, Biftu, Tesfaye, Greenlee, William J, Chintala, Madhu, Maletic, Milana, Zhu, Zhaoning
• Format: Article
• Language: English
• Subjects: Animals; Humans; Lactones; Myocardial Infarction - drug therapy; Platelet Aggregation Inhibitors; Rats; Receptor, PAR-1; Receptors, Proteinase-Activated; Thrombosis - chemically induced; Thrombosis - drug therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02048

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure–activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.