NOVEL ANTITHROMBOTIC DRUGS IN DEVELOPMENT

Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarka ble efficacy is rather unexpected, as aspirin selectively inhibits pla telet aggregation mediated through activation of the arachidonic-throm boxane pathway, but not platelet aggregation induced by adenosine diph osphate (ADP), collagen and low levels of thrombin. This apparent para dox has stimulated investigations on the effect of aspirin on eicosano id-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggrega tion at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor anta gonists. The final step of all platelet agonists is the functional exp ression of glycoprotein (GP) IIb/IIIa on the platelet surface, which l igates fibrinogen to link platelets together as part of the aggregatio n process. Agents that interact between GPIlb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) cont aining the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and ot her adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of p rostacyclin, some of which are orally active, are also available. Thro mbin has a pivotal role in both platelet activation and fibrin generat ion. In addition to natural and recombinant human antithrombin III, di rect antithrombin III-independent thrombin inhibitors have been develo ped as recombinant hirudin, hirulog, argatroban, boroarginine derivati ves and single stranded DNA oligonucleotides (aptanes). Direct thrombi n inhibitors do not affect thrombin generation and may leave some 'esc aping' thrombin molecules unaffected. Inhibition of factor Xa can prev ent thrombin generation and disrupt the thrombin feedback loop that am plifies thrombin production.