PREPARATION AND EVALUATION OF PEG-BOUND THROMBIN INHIBITORS BASED ON 4-AMIDINOPHENYLALANINE

The dipeptide Mtr-Asp-D-Adf-Pip 10 represents a potent thrombin inhibi tor. In comparison to NAPAP, 10 exhibited improved tolerability and a longer half-life in vivo, i.e., 20 +/- 5 min. We have coupled aminopol yethyleneglycolmonomethylether of various molecular weights to the car boxyl moiety of 10 and evaluated their biological properties. First, M tr-Asp-OBu(t) was coupled to the amino group of the PEG employing TOTU as an activating agent. This was followed by the removal of the OBu(t ) protecting group and coupling of D-Adf-Pip using TOTU as well. The P EG-bound thrombin inhibitors showed inhibition constants vs. thrombin in the subnanomolar range, i.e., they were more active than the parent molecular 10. Moreover, the pegylated inhibitors exhibited a longer l asting effect in vivo. In rats the half-life of Mtr-Asn (PEG10000-OMe) -D-Adf-Pip 14 was determined to be 63 min. Mtr-Asn(PEG10000-OMe)-D-Adf -Pip 14 showed a half-life of 120 min in pigs. It could be concluded t hat these PEG-bound thrombin inhibitors may be employed as versatile d rugs for parenteral administration in treating thrombotic disorders.