Replies to post #58872 on Biotech Values

[iwfal]

Ok, now I'm locking in. The ideal clot is a composite material, where the role of the resin is most closely analagous to the fibrin and the role of the reinforcement material is platelets. Thanks.

PS If you look up definitions on the web, even mildly authoritative ones, anticoagulants include the class of antiplatelets. However the most authoritative ones do not. So, again, thanks.

[genisi]

Antiplatelet Drugs: Improving the therapeutic window

http://www.nature.com/nrd/journal/v8/n5/full/nrd2886.html

By Erika Kennington, May 2009

Antiplatelet therapies are commonly used to lower the risk of heart attack and stroke caused by the formation of blood clots containing aggregated platelets over ruptured or denuded atherosclerotic plaques (atherothrombosis). However, such therapies also impair normal platelet function, and this can cause prolonged or even fatal bleeding. Now, a ligand-based design strategy targeting a G protein-coupled receptor (GPCR) on platelets has been used to identify a novel antiplatelet agent that does not prolong bleeding and which might be used in combination with existing agents to provide more effective antiplatelet therapy.

Platelet aggregation is regulated by multiple GPCRs, ligands for which include thromboxane A2 (TXA2) and ADP. Currently, the most widely used antiplatelet therapies are aspirin, which inhibits the production of TXA2, and clopidogrel, which antagonizes the P2Y12 ADP receptor. Another platelet GPCR — the EP3 receptor for the inflammatory mediator prostaglandin E2 (PGE2) — has also recently been identified as having a key role in atherothrombosis by Fabre and colleagues (see Further reading). PGE2 production is increased in inflamed atherosclerotic plaques, but the healthy arterial wall produces negligible amounts of PGE2, suggesting that antagonizing the platelet EP3 system might not have detrimental effects on normal platelet function, unlike aspirin and P2Y12 antagonists.

To investigate this possibility, Singh et al. used a ligand-based design strategy to synthesize EP3 receptor antagonists. Following detailed structure–activity relationship studies, one compound (DG-041) was selected for further evaluation. DG-041 showed >1,000-fold selectivity for EP3 receptors in radioligand displacement assays against other PGE2 receptors, whereas it was inactive against a range of other GPCRs. Furthermore, it blocked the PGE2-mediated inhibition of cAMP production and inhibited the platelet aggregation response in both rat and human plasma.

The authors then compared the in vivo effects of DG-041 on platelet function and bleeding time with those of the P2Y12 antagonist clopidogrel. DG-041 completely inhibited platelet aggregation with no concurrent increase in bleeding time (even at high doses), indicating that EP3 blockade has a negligible effect on bleeding. Conversely, the minimum effective dose of clopidogrel required to inhibit platelet aggregation significantly increased bleeding time. Furthermore, PGE2 restored the aggregation response, indicating that the efficacy of P2Y12 antagonists is limited in the context of inflamed plaque.

Finally, as initial clinical trials of DG-041 are likely to require co-administration with current antiplatelet drugs, the effects of combining EP3 and P2Y12 antagonists were investigated. Adding DG-041 suppressed the PGE2 facilitation of platelet aggregation seen with clopidogrel alone and did not increase bleeding time, suggesting that co-administration of EP3 and P2Y12 antagonists could represent a superior antiplatelet therapy.


ORIGINAL RESEARCH PAPER

1. Singh, J. et al. Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. ACS Chem. Biol. 4, 115–126 (2009)