Synthesis and characterisation of novel thrombin inhibitors based on 4-amidinophenylalanine.

AbstractThrombin 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 β-naphthylsulphonylglycyl-D,L-4-amidino-phenyalaylpiperidide (NAPAF). NAFAP 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 ...