Thioester chromogenic substrates for human factor VIIa: substituted isocoumarins are inhibitors of factor VIIa and in vitro anticoagulants

• Published in: Thrombosis and haemostasis Vol. 64; no. 1; p. 133
• Main Authors: Kam, C M, Vlasuk, G P, Smith, D E, Arcuri, K E, Powers, J C
• Format: Journal Article
• Language: English
• Published: Germany 1990
• Subjects: Amino Acid Sequence; Anticoagulants; Chromogenic Compounds - metabolism; Coumarins - pharmacology; Esters; Factor VIIa - antagonists & inhibitors; Humans; Kinetics; Molecular Sequence Data; Partial Thromboplastin Time; Peptides - metabolism; Prothrombin Time; Sulfur - metabolism
• ISSN: 0340-6245
• DOI: 10.1055/s-0038-1647269

Arginine thiobenzyl esters are convenient chromogenic substrates of factor VIIa (Z-Arg-SBzl, Kcat/KM = 1,600 M-1 s-1) and were used to study the kinetics of inhibition of factor VIIa by several mechanism-based isocoumarin inhibitors of trypsin-like enzymes. Isocoumarin derivatives substituted with a 7-guanidino or 3-isothiureidopropoxy group were good inhibitors of factor VIIa and acted as anticoagulants in human and rabbit plasma. With normal citrated human plasma, 4-chloro-3-ethoxy-7-guanidinoisocoumarin (3) and 7-amino-4-chloro-3-(3-isothiureidopropoxy) isocoumarin (ACITIC, 6) prolonged the prothrombin time (PT) ca. two-fold and prolonged the activated partial thromboplastin time (APTT) more than 4.5-fold at 20-30 microM. Both compounds had smaller effects in rabbit plasma. The short half-life of ACITIC and related isocoumarins in plasma should make these compounds uniquely useful as anticoagulants in therapeutic situations where it is desirable to have anticoagulant effects for a short defined time period.