Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid

Abstract

The potency of [human] thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidine-carboxylic acid moiety. Ki values for bovine .alpha.-thrombin were 0.019 .mu.M with (2R,4R)-MQPA, 0.24 .mu.M with (2R,4S)-MQPA, 1.9 .mu.M with (2S,4R)-MQPA and 280 .mu.M with (2S,4S)-MQPA. (2R,4R)-MQPA of the 4 stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 .mu.M for trypsin, 210 .mu.M for factor Xa, 800 .mu.M for plasmin and 1500 .mu.M for plasma kallikrein. Examination of the potency of thrombin inhibition by arginine derivatives related to MQPA in structure suggested the presence of a specific binding site for the carboxamide portion (C-terminal side). The relative inhibitory potency of the 4 stereoisomers of MQPA for trypsin was nearly identical with that for thrombin, suggesting that the specific binding site for the carboxamide portion is present in both enzymes. Modification of thrombin by phosphopyridoxylation or the presence of heparin did not significantly alter the binding of MQPA.