Synthesis and comparison of tripeptidylfluoroalkane thrombin inhibitors.

Abstract

Fluorinated ketone thrombin inhibitors based on the peptide sequence methyl-(D)-Phe-Pro-Arg-CF2R were synthesized: MDL 73,446 (1, R = F); MDL 73,775 (2, R = CF3); and MDL 75,579 (3, R = CH2CH2CH3). These were shown to be highly effective, slow binding inhibitors of thrombin. Anticoagulant activity was dose-dependent with 3 > 2 > 1 at doubling thrombin time and APTT, respectively. Anticoagulant activity corresponded with efficacy in a platelet-dependent (FeCl3-induced) rat carotid artery thrombosis model. Arterial occlusion was dose-dependently prolonged with 3 > 2 > 1 at doubling the occlusion time.

• Authors: B Neises, R J Broersma, C Tarnus, F Piriou, J M Remy, C Lintz, E F Heminger, L W Kutcher
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 3 Issue 8 Pg. 1049-61 (Aug 1995) ISSN: 0968-0896 [Print] England
• PMID: 7582979 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anticoagulants
• Antithrombins
• Chlorides
• Ferric Compounds
• Fluorocarbons
• Indicators and Reagents
• Oligopeptides
• ferric chloride

Topics

• Amino Acid Sequence
• Animals
• Anticoagulants (chemical synthesis, chemistry, pharmacology)
• Antithrombins (chemical synthesis, chemistry, pharmacology)
• Blood Platelets (physiology)
• Carotid Artery Thrombosis (drug therapy, physiopathology)
• Chlorides
• Disease Models, Animal
• Ferric Compounds
• Fluorocarbons
• Indicators and Reagents
• Magnetic Resonance Spectroscopy
• Molecular Sequence Data
• Oligopeptides (chemical synthesis, chemistry, pharmacology)
• Rats