Design and synthesis of potent PAR-1 antagonists based on vorapaxar. Issue 8 (15th April 2020)

• Record Type: Journal Article
• Authors: Fan, Mengna; Han, Min; Xia, Yan; Zhang, Yingbin; Chu, Yang; Bai, Guirong; Li, Wei; Li, Ju; Zhao, Lihui; He, Yi; Ma, Xiaohui; Duan, Zhongyu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 8(2020)
• Publication Date: 2020-04-15
• Subjects: Vorapaxar analogues -- Antiplatelet -- PAR-1 antagonists -- Structure-activity relationships; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127046
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of novel vorapaxar analogues with different amino substitutes at the C-7, C-9a and aromatic substitutes at the C-4 position were designed, synthesized, and evaluated for their inhibitory activity to PAR-1. Several compounds showed good potency in antagonist activity based on the intracellular calcium mobilization assay and excellent pharmacokinetics profile in rats. Among these analogues, 3d exhibited excellent PAR-1 inhibitory activity (IC50 = 0.18 μM) and the lower ability to cross the blood-brain barrier compared with vorapaxar (IC50 = 0.25 μM). Compound 3d has the potential to be developed as a new generation of PAR-1 antagonists with a better therapeutic window.