Trelia J. Craft

D-Phe-Pro-p-Amidinobenzylamine: A potent and highly selective thrombin inhibitor

Abstract The design, synthesis, and enzyme inhibitory profile of D-Phe-Pro-p-Amidinobenzylamine are presented. This compound has inhibitory activity equivalent to D-Phe-Pro-Arg-H, two orders of magnitude more potent than D-Phe-Pro-Agmatine. The results indicate that binding energy provided by the covalent bond of a transition-state analog can be replaced with noncovalent interactions.

Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs

Abstract Analogs of D-Phe-Pro-Agmatine were assayed for inhibititory activity versus thrombin, trypsin, plasmin, n-tPA and urokinase. The X-ray structure of the thrombin/D-Phe-Pro-Agmatine co-crystal revealed that the agmatine and analogous arginals have very similar bound conformations.

Heparin reacts stoichiometrically with thrombin during thrombin inhibition in human plasma

The thrombin-induced clotting of human plasma is not inhibited by endogenous protease inhibitors (α2-antithrombin, α2-macroglobulin, α1-antitrypsin) even though these inhibitors are present in huge molar excess. However, when heparin is added into the plasma clotting system, the thrombin is instantaneously and stoichiometrically inhibited. Each mole of added heparin causes the immediate inhibition of exactly one mole of thrombin. When a 1:1 molar ratio of heparin:thrombin exists, 100% inhibition of the thrombin occurs. Obviously, heparin interacts with thrombin in a 1:1 molar fashion. We postulate that a 1:1 thrombin-heparin complex reacts rapidly with the excessive amount of α2-antithrombin in plasma (normally 2 × 10−6 M) to result in the inactive termolecular compound:(α2-antithrombin:thrombin:heparin). Therefore, at normal α2-antithrombin levels, the required therapeutic heparin level will be equal to the molar thrombin challenge in the patient.

N-substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors

Abstract We have prepared a series of tripeptide arginine aldehydes in which the P2 proline has been replaced with a variety of N -substituted glycines. The effects of these modifications on thrombin inhibitory potency and serine protease selectivity were evaluated.

Characterization of LY806303 as a potent and selective inhibitor of thrombin

Abstract Methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carboxylate (LY806303; 1) has been characterized as a novel, potent and selective inhibitor thrombin.