New Thrombin Inhibitors Based on D-CHA-PRO-Derivatives

Abstract

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 alkyl-ated at the N^δ-, N^ω- and N^ω'-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 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 P1-residue was replaced by a hydroxyl group. Although the inhibition constants of these phenol derivatives showed still remarkable potency (16, K_i= 130 nM), their activity in clotting assays was strongly reduced.

Key Words:

• Thrombin
• Enzyme inhibitors
• Anticoagulants
• Tripeptide
• Synthesis