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

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.

沃拉帕沙（Vorapaxar）是一款获批上市的药物，适用于降低有心肌梗死病史或外周动脉疾病患者的血栓性心血管事件发生风险。在沃拉帕沙被发现后，研究人员持续开展药物化学研究工作，以识别结构差异化的药物先导化合物。为此，研究人员采用沃拉帕沙的C环截短类似物开展了大规模构效关系研究，最终成功发现3种先导化合物，分别以编号13、14和23为代表。在上述先导化合物中，化合物14展现出优良的药代动力学特性与理想的脱靶效应谱，这为其开展探索性大鼠毒理学研究提供了坚实的支撑依据。