Abstract

SY13 New antiplatelet agents Hall 3 15:00 14th July, 2003 Session Type: Symposium Subject area: Invited Speaker Session title: New antithrombotic drugs Abstract: SY13 Authors: K. Clemetson University of Bern, Switzerland Antiplatelet agents continue to be dominated by aspirin and those acting against alphaIIbetab3 and P2Y12. While changes in dosing and administration as well as use of combinations may still improve the effectiveness of these agents there is a strong interest in the development of agents acting via novel receptors or pathways. Aspirin and clopidogrel are administered orally, while other drugs are only available by the intravenous route and are thus only applicable to acute situations. of intravenous antagonists of alphaIIbbeta3 include abciximab, eptifibatide, and tirofiban but oral drugs of this class are still lacking or are ineffective (or worse!). There have been lively arguments about the reasons for this and possible pharmacokinetic approaches to overcoming it. The narrow clinical window of this class together with the fact that they only act at a late stage in platelet activation still remain major stumbling blocks. Interest has thus turned to other possible targets. The P2Y12 receptor is well covered via the thienopyridine class, in particular clopidogrel, and much continues to be learnt about applications. Other drugs targeting this receptor are being developed but are not yet clinically available. Mice with the gene for PI3Kg deleted also show reduced responses to ADP but not other primary agonists suggesting a signaling pathway approach. The other major ADP receptor, P2Y1 does not have the same advantage of tissue restriction but both in vitro and in vivo studies with new drug entities directed to P2Y1 indicate that it may be a promising target. All of these are late stage or feed back receptors. There is great interest in the adhesion activation receptors, GPIb complex and GPVI, that both have the advantages of being involved early and restricted to platelets. Although no pharmaceutical-type drugs are yet available, studies with antibodies have indicated that blocking either of these receptors prevents thrombosis without causing excessive bleeding. Development of small molecule inhibitors is not a trivial exercise because there are no obvious clefts for specific binding and large surfacesurface interactions are involved. There remain a number of other targets which are interesting, because they are more involved in the proinflammatory pathways, such as CD154, where expression requires release. More obscure, but still intriguing, targets include growth-arrest specific gene 6 (Gas6) and its receptors, which seem to have a role in regulating platelet responses. file:///E|/working/LAXMI-PRASAD/WileyML-3G/deepak/31-Jan/Monday/Abstract%20SY13.html (1 of 2) [1/31/2014 3:45:32 PM]