The key element in the """"""""final common pathway"""""""" leading to stable platelet aggregation is fibrinogen binding to the platelet integrin, alplaIIbbeta3. alphaIIbbeta3 inhibitors, that prevent platelet aggregation and subsequent thrombus formation by blocking the interaction of alphaIIbbeta3 with its ligands, have proven efficacious in the treatment of ischemic coronary and carotid disease. However the use of these drugs in a chronic setting may be limited due to unwanted side-effects on bleeding. The focus of this Phase II application is to develop novel therapeutic regulators of alphaIIbbeta3 function, by modulating the integrin cytoplasmic domains themselves. Phase I studies identified a strategy for regulating integrin signaling by inhibiting tyrosine phosphorylation of the cytoplasmic domain of beta3. We postulate that compounds capable of inhibiting this cytodomain activity will disrupt alphaIIbbeta3 function thus having the potential to be a new class of anti-thrombotics. In the long term we will develop these novel inhibitors of alphaIIbbeta3 to offer improved therapy for the large population afflicted with ischemic cardiovascular diseases.
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