Discovery of quinazoline-benzothiazole derivatives as novel potent protease-activated receptor 4 antagonists with improved pharmacokinetics and low bleeding liability.

Protease-activated receptor 4 (PAR4) plays a critical role in the development of pathological thrombosis, and targeting PAR4 is considered a promising strategy for improving antiplatelet therapies. Here, we reported the design of a series of quinazoline-benzothiazole-based PAR4 antagonists using a scaffold-hopping strategy. Systematic structure-activity relationship exploration leads to the discovery of compounds 20f and 20g, which displayed optimal activity (h. PAR4-AP PRP IC = 6.39 nM and 3.45 nM, respectively) on human platelets and high selectivity for PAR4. Both of them also showed excellent metabolic stability in human liver microsomes (compound 20f, T = 249.83 min, compound 20g, T = 282.60 min) and favourable PK profiles in rats (compound 20f, T = 5.16 h, F = 50.5 %, compound 20g, T = 7.05 h, F = 27.3 %). More importantly, neither compound prolonged the bleeding time in the mouse tail-cutting model (10 mg/kg, p.o.). These results suggest that these compounds have great potential for use in antiplatelet therapies.