The hydrolytic removal of the fibrinopeptides from fibrinogen changes the properties of the protein in several respects. The previously water-soluble molecules now assemble to form a gel which can be redispersed in certain media.l The cleavage of the fibrinopeptides also causes unmasking of the crosslinking sites of the protein. Under the influence of fibrinoligase (activated fibrin-stabilizing factor; FSF * ) , the fibrin gel is rapidly cross-linked via the open sites, to form an insoluble structure. The new material is a polymeric network wherein the single fibrin molecules are held together by covalent bonds. Although only about two covalent bonds are formed per mole of fibrin," the process imparts great elasticity and mechanical strength to the clot by the additional changes that the protein undergoes as a consequence of the covalent bond formation.3 Partial inhibition of the cross-linking reaction by certain compounds results in a mechanically weaker fibrin with enhanced plasmin dige~tibility.'-~ It is thus conceivable that inhibitors of fibrin crosslinking could be valuable prophylacttic or therapeutic agents in thrombotic diseases. Presumed Pathway of Transpeptidation and Inhibition of Fibrin Cross-linkingIn 1962, Lorand and coworkers proposed that transpeptidation should be considered as a probable mechanism for cross-linking. In an overall sense, an amino group of one fibrin molecule would, under the catalytic influence of fibrinoligase, react as a nucleophile with an activated carbonyl group of a neighboring fibrin molecule forming an amide bond between the two fibrin units. Since each molecule would carry both amino and carbonyl groups, the chain of cross-linking would be propagated. Although several components may

A series of omegadibenzylaminoalkylamines and related compounds have been prepared and tested as inhibitors of fibrin cross-linking. This structural type was chosen in an attempt to develop noncompetitive inhibitors of fibrinoligase. By the combination of the dibenzylamino moiety at one end and the primary amino group at the other end of a polymethylene chain, the same compound could function both as a pseudo donor substrate and as a noncompetitive alkylating inhibitor. Some of the compounds, notably 74-79, are among the most active fibrinoligase inhibitors described. However, the data indicate that the compounds probably function only as pseudo donor inhibitors.

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BioassayS. The biological assays were carried out as previously described23 and the inhibitory activity of each compd is expressed in relation to that of monodansylcadaverine (activity of monodansylcadaverine = 100). Results and Discussion

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