Discovery of Potent Orally Active Protease-Activated Receptor 1 (PAR1) Antagonists Based on Andrographolide.

Protease-activated receptor-1 (PAR1), a G-protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound 39 as the best PAR1 inhibitor. The further in vitro and ex vivo antiplatelet aggregation assays of compound 39 indicated that compound 39 was a potent antiplatelet agent. In addition, this compound is metabolically stable and displays a favorable pharmacokinetic profile with an elimination half-life of 3.1 h, which could be treated as a promising candidate for further clinical development.