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 IC50 = 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, T1/2 = 249.83 min, compound 20g, T1/2 = 282.60 min) and favourable PK profiles in rats (compound 20f, T1/2 = 5.16 h, F = 50.5 %, compound 20g, T1/2 = 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. [Display omitted] •Starting from compound XZ-13, a series of quinazoline benzothiazole derivatives were designed and synthesized.•Compounds 20f and 20g were highly potent and selective PAR4 antagonists.•Compounds 20f and 20g exhibited excellent in vitro metabolic properties.•Compounds 20f and 20g have improved pharmacokinetics and do not prolong bleeding time in a mouse haemostasis model.