title: 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.affiliation: Marion Merrell Dow Research Institute, Strasbourg, France.
authors.forename: B
authors.initials: B
authors.lastname: Neises
authors.forename: R J
authors.initials: RJ
authors.lastname: Broersma
authors.forename: C
authors.initials: C
authors.lastname: Tarnus
authors.forename: F
authors.initials: F
authors.lastname: Piriou
authors.forename: J M
authors.initials: JM
authors.lastname: Remy
authors.forename: C
authors.initials: C
authors.lastname: Lintz
authors.forename: E F
authors.initials: EF
authors.lastname: Heminger
authors.forename: L W
authors.initials: LW
authors.lastname: Kutcher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000503:physiopathology*; D002712:Chlorides; D004195:Disease Models, Animal; D005290:Ferric Compounds; D005466:Fluorocarbons; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D002712:Chlorides; D005290:Ferric Compounds; D005466:Fluorocarbons; D007202:Indicators and Reagents; D009842:Oligopeptides; C024555:ferric chloride