Discovery of Potent Peptide-Mimetic Antagonists for the Human Thrombin Receptor, Protease-Activated Receptor-1 (PAR-1)

Author(s): Bruce E. Maryanoff, Han-Cheng Zhang, Patricia Andrade-Gordon, Claudia K. Derian

Journal Name: Current Medicinal Chemistry - Cardiovascular & Hematological Agents
Continued as Cardiovascular & Hematological Agents in Medicinal Chemistry

Volume 1 , Issue 1 , 2003


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 α-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-mimetic 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 α-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.

Keywords: thrombin receptor, protease-activated receptor, par, antagonist, indole, indazole, dipeptide urea, trap, sfllrn, tethered ligand

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2003
Page: [13 - 36]
Pages: 24
DOI: 10.2174/1568016033356724

Article Metrics

PDF: 22