Thrombin inhibitors. 2. Amide derivatives of N.alpha.-substituted L-arginine

Abstract

A series of N.alpha.-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N.alpha.-substituent was prepared and tested as inhibitors of the clotting activity of [animal] thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N.alpha.-dansyl-L-arginine amide were the most inhibitory of N-alkyl and N,N-dialkyl derivatives of N.alpha.-dansyl-L-arginine amide. Their inhibitory effect was as potent as that of N.alpha.-dansyl-L-arginine n-butyl ester, with an I50 [median inhibitory concentration] of 2 .times. 10-6 M. N.alpha.-Substituted naphthalenesulfonyl-L-arginine amide derivatives of 4-methyl- and 4-ethylpiperidine showed a potent inhibition with an I50 of 10-7 to 10-6 M. The most potent inhibitor in this study was 1-[N.alpha.-(4,6-dimethoxynaphthalene-2-sulfonyl)-L-arginyl]-4-methylpiperidine, with an I50 of 7.5 .times. 10-8 M. Arginine amide derivatives of 4-methyl- or 4-ethylpiperidine with tetralin or an O2-containing heterocyclic compound as a N.alpha.-substituent showed an inhibition with an I50 < 10-5 M. N-Monosubstituted derivatives of N.alpha.-dansyl-L-arginine amide were not hydrolyzed by thrombin and were hydrolyzed very slowly by trypsin, and N,N-disubstituted derivatives were not hydrolyzed by both enzymes.