New aromatic diamidines with central .alpha.-oxyalkane or .alpha.,.omega.-dioxyalkane chains. Structure-activity relations for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process
A series of omega-amidinophenylalkyl amidinophenyl ethers was synthesized and examined for inhibitory activity against trypsin, pancreatic kallikrein, and thrombin. Modifications of the compounds included lengthening of the alkane chain, variation in the position of the amidino groups, and substitution of halogen on the benzene rings. The compounds act as competitive reversible inhibitors, and many of them possess considerable potency. An outstanding trypsin inhibitor was found in 4-amidinophenylethyl 4 amidino-2-bromophenyl ether (compound 7) with a Ki value of 7.3 x 10(-8) M (pH 8.1, 37 degrees). A number of aromatic diamidines with a central dioxyalkane chain were similarly studied. Here, 1-(4-amidino-2-iodophenoxy)-5-(3-amidinophenoxy)pentane (compound 32) was a highly effective inhibitor of bovine thrombin (Ki = 1.1 x 10(-6) M), of human thrombin, and of the overall clotting process of human plasma.