Thrombin inhibitors have been thought to play a pivotal role in myocardial infarct and stroke incidences and their aftermath. Quite some time ago potent synthetic thrombin inhibitors became known based on peptide derivatives D-Phe-Pro-Arg and benzamidine. One of them, fairly well characterised was beta-naphthylsulphonylglycyl-D,L-4-amidino-phenylalanylpiperidi de (NAPAP). NAPAP was prone to being administered intravenously due to its short plasma half life. Drawbacks to this compound such as effects on histamine release and blood pressure may have obstructed its clinical use. Long half life and oral bioavailability would be desirable for prophylactic treatment of thrombotic disorders. We have used NAPAP as a template for new synthetic compounds to improve some characteristics of its profile. For screening purposes we have investigated fairly simple surrogate parameters, aspects that were considered to contribute to pharmacological effects. Potency was correlated to thrombin inhibition, side effects were addressed by specificity toward thrombin as well as reduction in basicity, and plasma half life was considered to be modulated by plasma stability of the compound. Oral bioavailability would be affected by instability during the passage through the gut wall. Chemical introduction of a carboxylic group and exchange of the naphthyl group for 4-methoxy-2,3,6-trimethylphenyl led to a compound that when compared to NAPAP, exhibited a 4-fold increase in thrombin inhibitory activity and a 3-fold increase in trypsin specificity. Plasma stability decreased to 22 h, however, sufficient enough not to play a major role in plasma half life. Gut homogenate stability of the compound has not changed. The potency increase did not translate into a reduction in IC50-values for the coagulation assay aPTT and TT, in contrast to the IC50-values for thrombin-induced platelet aggregation.