Inhibition of C1r, C1s and generation of C1s by amidino compounds.

A series of amidino compounds has been investigated for their inhibitory effects on C1s, C1r, and generation of C1s. Diamidines consisting of two amidinophenyl residues linked in para position by a molecular bridge proved to be the strongest competitive inhibitors of C1s, whereas those linked in meta position were the strongest competitive inhibitors of C1r. They inhibited the overall generation of C1s when added to the system containing three subunits of C1 and Ca2+. Diphenylamidines were more active than single ring amidines. Of all the compounds tested, dibromopropamidine was the most effective inhibitor of C1s with Ki value 3 x 10(-5) M and deltaF' values 6.4 kcal x mole(-1), whereas amicarbalide and M and B 4596 were the strongest inhibitors of C1r with Ki values 3.5 x 10(-5) M and 3.25 x 10(-5) M and deltaF' values 6.3 and 6.34 kcal x mole(-1), respectively. Epsilon-Aminocaproic acid was also included in this study for comparison purposes and was found to be inert as to its effects on these reactions. The possibility that some of these amidino compounds might prove to be useful for treatment of hereditary angioneurotic edema is discussed.