Novel bis(benzamidino) compounds with an aromatic central link. Inhibitors of thrombin, pancreatic kallikrein, trypsin, and complement

Abstract

A series of novel aromatic diamidines was synthesized and evaluated for antiproteolytic activity. The compounds were distinguished by inclusion of an aromatic ring structure, either benzene or bisbenzene or naphtholene, in the link between 2 amidinobenzene moieties. A highly potent inhbitor of bovine thrombin was discovered in .alpha.,.alpha.-bis(4-amidino-2-iodophenoxy)-p-xylene with a Ki value of 1.1 .times. 10-7 M (pH 8.1, 37.degree.), while .alpha.,.alpha.-bis(4-amidino-2-iodophenoxy)-m-xylene was an outstanding inhibitor of porcine pancreatic kallikrein (Ki = 3.1 .times. 10-8 M). Several of the compounds investigated also demonstrated a considerable blocking effect on trypsin and on the complement-dependent immune lysis of red cells.