Conformationally restricted analogs of the direct thrombin inhibitor FM 19.

The serine protease thrombin plays several key roles in the clotting cascade within the hemostatic system, such as in fibrin formation and platelet activation. Thus, development of an inhibitor that binds to the enzyme's active site (a direct thrombin inhibitor) offers an approach for the treatment of thrombus-associated diseases. Previous structure-activity relationship studies originally based on the bradykinin breakdown product Arg-Pro-Pro-Gly-Phe (RPPGF) led to the development of lead compound FM 19 (d-Arg-Oic-Pro-d-Ala-Phe(p-Me)-NH(2)).

Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19.

Myocardial ischemia and other acute coronary syndromes are leading causes of death worldwide, and often result from a thrombus that blocks an atherosclerotic coronary artery. A key enzyme in thrombus formation is the serine protease thrombin, which is responsible for both the conversion of soluble fibrinogen into insoluble fibrin, as well as the activation of the GPCRs, PAR1 and PAR4, which stimulate platelet aggregation. Thus, thrombin is an attractive target for anticoagulant and antithrombotic therapy.