title: p-Amidino esters as irreversible inhibitors of factors IXa and Xa and thrombin.
abstract: A number of inhibitors of thrombin and factor Xa have been described; however, only one inhibitor of factor IXa has been reported. This compound, dansyl-Glu-Gly-Arg chloromethyl ketone (DEGER), inhibits porcine factor IXa with a second-order rate constant of 2.2 X 10(4) M-1 min-1. We now describe the synthesis and characterization of three p-amidinophenyl esters that inhibit human factor IXa with second-order rate constants comparable to those observed with human and bovine factor Xa and alpha-thrombin. These rate constants of inhibition, moreover, are 2-30-fold greater than observed when DEGER is employed to inhibit porcine factor IXa. Additional advantages of these derivatives include their ease of synthesis and low degree of toxicity. The p-amidinophenyl ester of benzoic acid was employed to inhibit human factor IXa, and the plasma clearance of the protein was studied in mice. These experiments demonstrate for the first time that the endothelial binding previously reported with factor IXa is independent of the active site, a finding similar to the behavior observed with factor Xa and alpha-thrombin in this and previous reports.
mesh_terms: D000215:Acylation; D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology*; D005164:Factor IX / Q000037:antagonists & inhibitors*; D015949:Factor IXa; D005170:Factor X / Q000037:antagonists & inhibitors*; D015951:Factor Xa; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; D001550:Benzamidines; D001565:Benzoates; D002934:Cinnamates; D007202:Indicators and Reagents; C050358:4-amidinophenyl cinnamate; C050359:4-amidinophenyl 2-methylcinnamate; C006491:4-amidinophenylbenzoate; D005164:Factor IX; D005170:Factor X; D015949:Factor IXa; D013917:Thrombin; D015951:Factor Xa