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.