PHARMACOLOGICAL AND BIOCHEMICAL PROFILES OF NEW VENOUS ANTITHROMBOTICBETA-D-XYLOSIDE DERIVATIVES - POTENTIAL ANTIATHERO THROMBOTIC DRUGS/

Following a screening program for orally active antithrombotic drugs, it was found that a series of thioxyloside compounds presented with go od venous antithrombotic properties. Of more than 500 compounds, LF 09 -0055, LF 04-0212, and LF 05-0030 were the most active at inhibiting v enous thrombus formation in the rat and rabbit Wessler model after int ravenous and oral dosing. LF 05-0030 showed the greatest activity with an ED(80) value of 6 mg/kg on oral administration in rats. This activ ity was maintained in several different models of venous thrombosis an d shown to be devoid of anticoagulant effects or hemorrhage. Kinetic s tudies have demonstrated that maximal levels of activity, following ei ther 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 capa ble of initiating glycosaminoglycan (GAG) synthesis. Moreover, in vitr o galactosyltransferase 1 (the second enzyme involved in GAG polymeriz ation) enzymic assays showed that these thioxyloside derivatives were good accepters for galactose transfer and therefore at initiating GAG formation. Further in vivo experimentation demonstrated that after tre atment by these molecules an important elevation in circulating GAG oc curred, with LF 05-0030 presenting the greatest activity, being five t imes higher than control levels. In addition it was found that dermata n sulfate levels, expressed as antithrombin activity by heparin cofact or II, were significantly increased over control values. As such, this dermatan sulfate moiety is believed to support the antithrombotic act ivity observed. Studies are underway to investigate the activity of th ese interesting molecules in atherosclerosis and other vessel wall dis eases.