Small molecular inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism

There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease specifically with minimal effects on normal hemostasis. We targeted integrin α2β 1, a collagen receptor, because its overexpression is associated with pathological clot formation while its absence does not cause severe bleeding. Structure-activity studies led to the development of highly potent and selective small molecule inhibitors. The responses of integrin α2β 1 mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I domain-containing integrins. One of the potent compounds was proven efficacious in an animal model of arterial thrombosis, which is the first demonstration of in vivo efficacy for inhibition of this platelet receptor. These results suggest targeting integrin α2β1 could be a potentially safe, effective approach to long term therapy for cardiovascular disease