Progress toward a Glycoprotein VI Modulator for the Treatment of Thrombosis.

Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.