Biochemical studies on sulfated lactobionic acid amides.
A series of sulfated bis-lactobionic acid amides was prepared. The compounds comprise highly charged poly-anions of very low molecular weight. Usually, the compounds contain 16 sulfate groups per molecule and are homogeneous, monodisperse substances. The molecular weights range from 2388 to 2514. The compounds were evaluated for anticoagulant activity using a number of standard tests. The compounds exhibited moderate to good APTT activity. Interestingly, the anti-Xa and anti-IIa activities were very low, particularly in amidolytic assays. Using prothrombin and Factor X activation assays, it was demonstrated that these compounds were more potent in these experimental settings than in standard anti-Xa or anti-IIa assays. Compared with heparin and LMW heparins, the bis-lactobionic acid amides were particularly active as inhibitors of the intrinsic system activation of Factor X. The bis-lactobionic acid amides exhibited potent anticomplement activity, being clearly superior to heparin and LMW heparins. For the most interesting substance, LW 10082, experimental results suggest that its anticoagulant activity is independent of antithrombin II. The anticoagulant activity of LW 10082 was readily neutralized by protamine sulfate. Platelet factor 4, however, did not reduce its anticoagulant activity. Because of these favorable properties, it is hoped that LW 10082 might prove to be an interesting alternative to heparin or LMW heparin in clinical use.
Klauser
R J
RJ
Department of Chemistry, Luitpold-Werk, München, Germany.
Meinetsberger
E
E
Raake
W
W
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D002240:Carbohydrate Sequence; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015951:Factor Xa / Q000096:biosynthesis; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013464:Sulfuric Acids / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D000925:Anticoagulants; D003169:Complement Inactivator Proteins; D004187:Disaccharides; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D013464:Sulfuric Acids; D006493:Heparin; D015951:Factor Xa