Synthesis and comparison of tripeptidylfluoroalkane thrombin inhibitors.
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.
Neises
B
B
Marion Merrell Dow Research Institute, Strasbourg, France.
Broersma
R J
RJ
Tarnus
C
C
Piriou
F
F
Remy
J M
JM
Lintz
C
C
Heminger
E F
EF
Kutcher
L W
LW
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
D000925:Anticoagulants; D000991:Antithrombins; D002712:Chlorides; D005290:Ferric Compounds; D005466:Fluorocarbons; D007202:Indicators and Reagents; D009842:Oligopeptides; C024555:ferric chloride