Key result
Novel PAR-1 antagonists show antirestenotic and antithrombotic activity via direct receptor inhibition in preclinical models.
Why the study?
PAR-1 is involved in hemostasis, proliferation, and tissue injury, but potent, selective antagonists to delineate its physiological and pathophysiological roles were needed.
The discovery of potent PAR-1 antagonists RWJ-56110 and RWJ-58259 demonstrates their ability to block thrombin receptor activation and shows potential for treating thrombosis and restenosis in preclinical models.
De novo PAR-1 design is hypothesis-generating; leaves open clinical translation pending validation.
Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease alpha-thrombin, is expressed in various tissues (e.g. platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. By using a de novo design approach, we have discovered a series of potent heterocycle-based peptide-miimetic antagonists of PAR-1, exemplified by advanced leads RWJ-56110 (22) and RWJ-58259 (32). These compounds are potent, selective PAR-1 antagonists, devoid of PAR-1 agonist and thrombin inhibitory activity: they bind to PAR-1, interfere with calcium mobilization and cellular functions associated with PAR-1, and do not affect PAR-2, PAR-3, or PAR-4. RWJ-56110 was determined to be a direct inhibitor of PAR-1 activation and internalization, without affecting PAR-1 N-terminal cleavage. At high concentrations of alpha-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, but not in human platelets; whereas, at high concentrations of TRAP-6, RWJ-56110 blocked activation responses in both cell types. This result is consistent with the presence of another thrombin receptor on human platelets, namely PAR-4. RWJ-56110 and RWJ-58259 clearly interrupt the binding of a tethered ligand to its receptor. RWJ-58259 demonstrated antirestenotic activity in a rat balloon angioplasty model and antithrombotic activity in a cynomolgus monkey arterial injury model. Such PAR-1 antagonists should not only serve as useful tools to delineate the physiological and pathophysiological roles of PAR-1, but also may have therapeutic potential for treating thrombosis and restenosis in humans.
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Maryanoff et al. (2003) studied Thrombosis and restenosis. PAR-1 antagonists (RWJ-56110 and RWJ-58259) was evaluated. The novel peptide-mimetic PAR-1 antagonists RWJ-56110 and RWJ-58259 demonstrated direct inhibition of PAR-1 activation, with antirestenotic and antithrombotic activity in animal models.
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