1. Discovery of quinazoline-benzothiazole derivatives as novel potent protease-activated receptor 4 antagonists with improved pharmacokinetics and low bleeding liability.
- Author
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Li S, Liu S, Yuan D, Liu R, Hu L, and Zhu X
- Subjects
- Animals, Humans, Structure-Activity Relationship, Mice, Rats, Molecular Structure, Drug Discovery, Hemorrhage chemically induced, Hemorrhage drug therapy, Dose-Response Relationship, Drug, Microsomes, Liver metabolism, Microsomes, Liver chemistry, Male, Platelet Aggregation Inhibitors pharmacology, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors pharmacokinetics, Rats, Sprague-Dawley, Platelet Aggregation drug effects, Quinazolines chemistry, Quinazolines pharmacology, Quinazolines chemical synthesis, Quinazolines pharmacokinetics, Benzothiazoles chemistry, Benzothiazoles pharmacology, Benzothiazoles chemical synthesis, Benzothiazoles pharmacokinetics, Receptors, Thrombin antagonists & inhibitors, Receptors, Thrombin metabolism
- Abstract
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
50 = 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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