Abstract
Following a screening program for orally active antithrombotic drugs, it was found
that a series of thioxyloside compounds presented with good venous antithrombotic
properties. Of more than 500 compounds, LF 09-0055, LF 04-0212, and LF 05-0030 were
the most active at inhibiting venous thrombus formation in the rat and rabbit Wessler
model after intravenous and oral dosing. LF 05-0030 showed the greatest activity with
an ED80 value of 6 mg/kg on oral administration in rats. This activity was maintained in
several different models of venous thrombosis and shown to be devoid of anticoagulant
effects or hemorrhage. Kinetic studies have demonstrated that maximal levels of activity,
following either intravenous or oral dosing, occurred between 2 and 4 hours after
administration. This may reflect the type of mechanism involved, since it has been
well documented in the literature that xylosides are capable of initiating glycosaminoglycan
(GAG) synthesis. Moreover, in vitro galactosyltransferase 1 (the second enzyme involved
in GAG polymerization) enzymic assays showed that these thioxyloside derivatives were
good acceptors for galactose transfer and therefore at initiating GAG formation. Further
in vivo experimentation demonstrated that after treatment by these molecules an important
elevation in circulating GAG occurred, with LF 05-0030 presenting the greatest activity,
being five times higher than control levels. In addition it was found that dermatan
sulfate levels, expressed as antithrombin activity by heparin cofactor II, were significantly
increased over control values. As such, this dermatan sulfate moiety is believed to
support the antithrombotic activity observed. Studies are underway to investigate
the activity of these interesting molecules in atherosclerosis and other vessel wall
diseases.
Keywords:
Thioxylosides - venous antithrombotic - heparin cofactor II - glycosaminoglycans -
galactosyltransferase 1
