Diarylamidine derivatives with one or both of the aryl moieties consisting of an indole or indole-like ring. Inhibitors of arginine-specific esteroproteases

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Abstract
A series of 62 diarylamidine derivatives was evaluated for their antiproteolytic activity. In all but 2 of the compounds 1 or both of the amidino-substituted aryl moieties was an indole or an indole-like ring. The latter included indene, benzimidazole, benzofuran, benzo[.beta.]thiophene and several other related nitrogen-containing heterocycles. Several compounds exhibited considerable inhibitory potency against thrombin, trypsin and pancreatic kallikrein. An outstanding inhibitor of trypsin was bis(5-amidino-2-benzimidazolyl)methane (compound 42) with a Ki value of 1.7 .times. 10-8 M (pH. 8.1, 37.degree. C). Another derivative, 1,2-di(4-amidino-2-benzofuranyl)ethane (compound 21), apparently was a highly effective inhibitor of the overall blood clotting process. From a general structure-activity standpoint these compounds demonstrate that minor structural variations of low-molecular-weight inhibitors can result in significant changes in specificity and potency with regard to antiproteolytic activity.