Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potency of thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfony l]- L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidinecarboxylic acid moiety. Ki values for bovine alpha-thrombin were 0.019 microM with (2R,4R)-MQPA, 0.24 microM with (2R,4S)-MQPA, 1.9 microM with (2S,4R)-MQPA, and 280 microM with (2S,4S)-MQPA. (2R,4R)-MQPA of the four stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 microM for trypsin, 210 microM for factor Xa, 800 microM for plasmin, and 1500 microM 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 four 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.
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PMID:Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl++ +) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid. 669 68

A short history of the research work of S. Okamoto and co-workers, for the previous 50 years, is briefly described. In the 1950s, when the physiologic role of fibrinolysis had not been established, they began to seek for compounds that inhibit the action of plasmin. They examined approximately 200 lysine derivatives and discovered epsilon aminocaproic acid (EACA) and tranexamic acid (t-AMCHA). In the 1970s, we selected thrombin as the target enzyme to be controlled; structure-activity relationship studies, taking arginine as the skeleton structure, led to the discovery of the selective thrombin inhibitor No. 205 (4-ethyl-1-[N2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]- 1-piperidine), and further attempts to minimize the toxicity finally led to No. 805 (argatroban, MD-805, (2R,4R)-4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfo nyl]-L-arginyl)-2-piperidine carboxylic acid). Argatroban, without any cofactor, inhibits thrombin competitively. The high selectivity of the action of argatroban is promising for treating thrombosis in clinical practice. More recently, taking advantage of our knowledge obtained through previous studies, active center-directed plasmin inhibitors and a selective inhibitor of kallikrein have been found.
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PMID:Enzyme-controlling medicines: introduction. 946 21