title: Comparative studies in vitro and ex vivo on the anticoagulant effect of a reversible and an irreversible tripeptide inhibitor of thrombin.
abstract: Comparative studies on the anticoagulant effect of D-Phe-Pro-Arg-H (ALD) and D-Phe-Pro-Arg-CH2Cl (CMK) were carried out in order to estimate whether the reversible or the irreversible tripeptide inhibitor of thrombin would be more suitable to develop as a novel anticoagulant. Conventional screening assay methods in vitro were focused on the functional stability of the compounds in whole blood and blood components while ex vivo the changes in whole blood clotting time under parenteral application of the inhibitors were investigated. The efficacy of ALD relative to that of CMK was found to depend on the complexity of the test systems. Thus CMK was the more inhibitory in citrated plasma, but ALD showed the higher potency in whole blood. When incubated in various systems such as human whole blood, serum, solutions of isolated plasma proteins, digestive juices and tissue homogenates, respectively, the inhibitory activity of ALD showed only slight decreases for several hours while marked or substantial loss of activity was observed with CMK under identical conditions. ALD administered parenterally to rabbits proved to be powerful anticoagulant; CMK exhibited only a weak and transient anticoagulant effect presumably due to its ability to bind irreversibly to various plasma and tissue proteins. Accordingly, the reversible inhibitor ALD should be more suitable to develop as an anti-coagulant than CMK, its irreversibly acting analogue.
authors.affiliation: Institute for Drug Research, Budapest, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Bagdy
authors.forename: E
authors.initials: E
authors.lastname: Barabás
authors.forename: S
authors.initials: S
authors.lastname: Bajusz
authors.forename: E
authors.initials: E
authors.lastname: Széll
authors.forename: A
authors.initials: A
authors.lastname: Fehér
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D005750:Gastric Juice / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D009842:Oligopeptides; C020924:phenylalanyl-prolyl-arginine methyl chloride; C077952:phenylalanyl-prolyl-arginine; D013917:Thrombin