Thrombin Inhibitors. 2. Amide Derivatives of Nα-Substituted L-Arginine

Article abstract of DOI:10.1021/jm00182a004

A series of N^α-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N^α-substituent was prepared and tested as inhibitors of the clotting activity of thrombin.N-n-Butyl and N-n-butyl-N-methyl derivatives of N^α-dansyl-L-arginine amide were the most inhibitory of N-alkyl and N,N-dialkyl derivatives of N^α-dansyl-L-arginine amide.Their inhibitory effect was as potent as that of N^α-dansyl-L-arginine n-butyl ester, with an I50 of 2*10^-6 M.N^α-Substituted naphthalenesulfonyl-L-arginineamide derivatives of 4-methyl- and 4-ethylpiperidine also showed a potent inhibition with an I50 of 10^-7 to 10^-6 M.The most potent inhibitor in this study was 1-α-(4,6-dimethoxynaphthalene-2-sulfonyl)-L-arginyl>-4-methylpiperidine, with an I50 of 7.5*10^-8 M.Arginine amide derivatives of 4-methyl- or 4-ethylpiperidine with tetralin or an oxygen-containing heterocyclic compound as a N^α-substituent showed an inhibition with an I50 less than 10^-5 M.N-Monosubstituted derivatives of N^α-dansyl-L-arginine amide were not hydrolyzed at all by thrombin and were hydrolyzed very slowly by trypsin, and N,N-disubstituted derivatives were not hydrolyzed at all by both enzymes.