New thrombin inhibitors based on D-Cha-Pro-derivatives

A series of new analogs with modifications in the C-terminal residue were p repared based on the known thrombin inhibitor D-Phe-Pro-agmatine. These inc lude several compounds alkyl ated at the N-delta-, N-omega- and N-omega'-at oms of the guanidino group and a number of inhibitors derived from commerci ally available diamines. All analogs with alkylation of the guanidino group showed very poor activity. In contrast, the most potent and selective inhi bitor with a cyclic and basic residue in the Pi-position was found to be Ph -CH2-SO2-D-Cha-Pro-4-(amidomethyl) amidinopiperidine 11 with a K-i of 0.27 nM. In addition, a number of compounds were synthesized, in which the basic amidino group of the Pi-residue was replaced by a hydroxyl group. Although the inhibition constants of these phenol derivatives showed still remarkab le potency (16, K-i = 130 nM), their activity in clotting assays was strong ly reduced.