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. Previous studies in our laboratory led to the development of lead compound FM 19 (D-Arg-Oic-Pro-D-Ala-Phe(p-Me)-NH2), which shows modest potency as a thrombin inhibitor. The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed potential sites for modification to improve potency. This study reports replacements to the first residue (D-Arg1) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9, with improved alpha-thrombin inhibition (IC50 values of 0.66 +/- 0.20 microM and 0.57 +/- 0.12 microM, respectively).