Synthesis of isosteres of p-amidinophenylpyruvic acid. Inhibitors of trypsin thrombin, and pancreatic kallikrein.
A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the most effective inhibitor of the enzymes in question, with a potency (Ki = 3.16 x 10-6 M vs. trypsin; Ki = 4.8 x 10-5 M vs. thrombin) similar to that of p-amidinophenylpyruvic acid (Ki = 6.0 x 10-6 M vs. trypsin; Ki = 2.0 x 10-5 M vs. thrombin). Ethyl 4-amidino-2-iodophenoxyacetate was also found to be the most effective in blocking the clotting activity of plasma, as indicated by significant prolongation of the partial thromboplastin time. This paper reports the synthetic methods, the enzyme inhibitory activity, and the structure-activity relationships observed.
D000578:Amidines / Q000138:chemical synthesis; D001780:Blood Coagulation Tests; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D010667:Phenylpyruvic Acids / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013925:Thromboplastin; D014361:Trypsin Inhibitors / Q000138:chemical synthesis*
D000578:Amidines; D010667:Phenylpyruvic Acids; D014361:Trypsin Inhibitors; D013925:Thromboplastin; D007610:Kallikreins; D013917:Thrombin