Thrombin receptors and their antagonists: an update on the patent literature

Thrombin plays a central role in cardiovascular inflammation. Most of the cellular responses to thrombin are mediated by cell surface protease-activated receptors (PARs). Several preclinical studies indicate that PARs are potential targets for treating cardiovascular diseases such as thrombosis, atherosclerosis and restenosis. Among PARs, PAR-1 has emerged as an important therapeutic target.

This review covers recent advances in the development of thrombin receptors antagonists. It is focused on the search for PAR-1 antagonists as this is at the moment the most promising and attractive target. However, some early promising studies on PAR-3 and -4 antagonists are also reported.

The review has been written in order to give to the reader hints and references that cover, in our opinion, the most interesting and/or promising approaches in this research field.

Research on PAR-1 antagonists has finally led to good clinical candidates such as SCH-530348 (Schering-Plough) and E-5555 (Eisai Co.). Clinical trials clearly demonstrate that development of PAR1 antagonists is not only possible but most likely will lead to development of antiplatelet drugs as well as of drugs useful for the treatment of inflammatory, proliferative and neurodegenerative diseases.