The synthesis of arginylfluoroalkanes, their inhibition of trypsin and blood-coagulation serine proteinases and their anticoagulant activity.

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  • Author(s): Ueda T;Ueda T; Kam CM; Powers JC
  • Source:
    The Biochemical journal [Biochem J] 1990 Jan 15; Vol. 265 (2), pp. 539-45.
  • Publication Type:
    Journal Article; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Print ISSN: 0264-6021 (Print) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
    • Subject Terms:
      Anticoagulants/*chemical synthesis ; Ketones/*chemical synthesis ; Serine Endopeptidases/*blood ; Trypsin Inhibitors/*chemical synthesis; Amino Acid Sequence ; Arginine ; Fluorine ; Humans ; Indicators and Reagents ; Ketones/pharmacology ; Kinetics ; Magnetic Resonance Spectroscopy ; Molecular Sequence Data ; Oligopeptides ; Partial Thromboplastin Time ; Prothrombin Time ; Serine Proteinase Inhibitors ; Structure-Activity Relationship
    • Abstract:
      Seven arginylfluoroalkanes ('arginine fluoroalkyl ketones') were synthesized by using a modified Dakin-West procedure. The structure of benzoyl-Arg-CF2CF3 was analysed by 19F-n.m.r. spectroscopy and m.s. and the compound was shown to exist primarily as a hydrate or cyclic carbinolamine. Arginylfluoroalkanes are good inhibitors of blood-coagulation serine proteinases and were found to be slow-binding inhibitors for bovine trypsin with Ki values of 0.2-56 microM. Benzoyl-Arg-CF2CF3 was the best inhibitor for bovine thrombin and human Factor XIa, and inhibited thrombin and Factor XIa competitively with Ki values of 13 microM and 62 microM respectively. The best inhibitor for pig pancreatic kallikrein was p-toluoyl-Arg-CF3, with a Ki value of 35 microM. Benzoyl-Arg-CF3 and benzoyl-Arg-CF2CF3 inhibited human plasma kallikrein competitively, with Ki values of 50 microM. None of the seven arginylfluoroalkanes was a good inhibitor of human factor Xa or of Factor XIIa. The arginylfluoroalkanes were tested in the prothrombin time (PT) and activated partial thromboplastin time (APTT) coagulant assays. Two fluoroketones, benzoyl-Arg-CF2CF3 and 1-naphthoyl-Arg-CF3, had significant anticoagulant activity. Benzoyl-Arg-CF2CF3 was found to prolong the PT 1.8-fold at 120 microM and to prolong the APTT 2.4-fold at 90 microM, whereas 1-naphthoyl-Arg-CF3 only prolonged the APTT 1.7-fold at 100 microM.
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    • Grant Information:
      HL 34035 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Anticoagulants)
      0 (Indicators and Reagents)
      0 (Ketones)
      0 (Oligopeptides)
      0 (Serine Proteinase Inhibitors)
      0 (Trypsin Inhibitors)
      284SYP0193 (Fluorine)
      94ZLA3W45F (Arginine)
      EC 3.4.21.- (Serine Endopeptidases)
    • Publication Date:
      Date Created: 19900115 Date Completed: 19900313 Latest Revision: 20190501
    • Publication Date:
      20221208
    • Accession Number:
      PMC1136917
    • Accession Number:
      10.1042/bj2650539
    • Accession Number:
      2302184