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Thromb Haemost 1990; 64(01): 133-137
DOI: 10.1055/s-0038-1647269
Original Article
Schattauer GmbH Stuttgart

Thioester Chromogenic Substrates for Human Factor VIIa: Substituted Isocoumarins Are Inhibitors of Factor VIIa and In Vitro Anticoagulants

Chih-Min Kam
1   The School of Chemistry, Georgia Institute of TechnologyAtlanta, GA, and Merck, U.S.A.
,
George P Vlasuk
2   Sharp & Dohme Research Laboratories, West Point, PA, U.S.A.
,
Donna E Smith
2   Sharp & Dohme Research Laboratories, West Point, PA, U.S.A.
,
Karen E Arcuri
2   Sharp & Dohme Research Laboratories, West Point, PA, U.S.A.
,
James C Powers
1   The School of Chemistry, Georgia Institute of TechnologyAtlanta, GA, and Merck, U.S.A.
› Author Affiliations
Further Information

Publication History

Received 26 June 1989

Accepted after revision 02 April 1990

Publication Date:
04 September 2018 (online)

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Summary

Arginine thiobenzyl esters are convenient chromogenic substrates of factor Vila (Z-Arg-SBzl, kcat/KM = 1,600 M−1 s−1) and were used to study the kinetics of inhibition of factor Vila 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 Vila 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-isothiurei-dopropoxy) 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 pM. 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.

 

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