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New thrombin inhibitors based on D-cha-Pro-derivatives.

A series of new analogs with modifications in the C-terminal residue were prepared based on the known thrombin inhibitor D-Phe-Pro-agmatine. These include several compounds alkylated at the N delta-, N omega- and N omega'-atoms of the guanidino group and a number of inhibitors derived from commercially available diamines. All analogs with alkylation of the guanidino group showed very poor activity. In contrast, the most potent and selective inhibitor with a cyclic and basic residue in the P1-position was found to be Ph-CH2-SO2-D-Cha-Pro-4-(amidomethyl) amidinopiperidine 11 with a Ki of 0.27 nM. In addition, a number of compounds were synthesized, in which the basic amidino group of the P1-residue was replaced by a hydroxyl group. Although the inhibition constants of these phenol derivatives showed still remarkable potency (16, Ki = 130 nM), their activity in clotting assays was strongly reduced.