Platelet aggregating agents

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

Mechanism of Action A hematologic agent that reduces platelet production and prevents platelet shape changes caused by platelet aggregating agents. Therapeutic Effect Inhibits platelet aggregation. 

Ticlopidine (Figure 7.3), another substituted thiophene that is clinically utilized as an anti-platelet aggregation agent, is reportedly the first selective mechanism-based inactivator of CYP2C19 . This inactivation apparently occurs during S-oxidation of the thiophene moiety. The failure of GSH (5 mM) to inhibit ticlopidine-mediated... 

Dismption of the endothehal surface of blood vessels expose coUagen fibers and connective tissue. These provide surfaces that promote platelet adherence, platelet release reaction, and subsequent platelet aggregation. Substances Hberated from the platelets stimulate further platelet aggregation, eg, adenosine diphosphate maintain vasoconstriction, eg, serotonin and participate in blood coagulation, eg, platelet Factors III and IV. In addition, the release reaction modifies platelet membranes in a manner that renders phosphoHpid available for coagulation. The thrombin [9002-04-4] elaborated by the coagulation mechanism is a potent agent in the induction of the platelet release reaction. 

Degrades ADP (an aggregating agent of platelets) to AMP -t P Inhibits platelet adhesion and aggregation by elevating levels of cGMP... 

Thrombin and other agents cause platelet aggregation, which involves a variety of biochemical and morphologic events. Stimulation of phosphofipase C and the polyphosphoinositide pathway is a key event in platelet activation, but other processes are also involved. 

The widely used platelet inhibitor aspirin or acetylsalicylic acid, by acetylating the enzyme cyclooxygenase, inhibits platelet function by preventing the formation of thromboxane A2 and the synthesis of prostaglandin I2 (PGI2) (68). Aspirin has been used in combination with other antiplatelet agents such as ticlopidine, which inhibits ADP-induced platelet aggregation (69). 

Because of the resonance stabilization possible in its deprotonated form, the 5-tetrazolyl moiety is actually nearly as acidic (pKa ca. 6) as many carboxylic acids. This has led to its inclusion in many drug series as a carboxyl surrogate. Apparently related in concept to indomethacin (26a), intrazole (26) is a nonsteroidal antiinflammatory agent which also inhibits platelet aggregation, and therefore is of potential value in keeping the contents of the... 

Aspirin is maximally effective as an antithrombotic agent at the comparatively low dose of 81 to 325 mg per day. (The antipyretic dose of aspirin in adults is 325 to 650 mg every 4 h.) Higher doses of aspirin are actually contraindicated in patients prone to thromboembolism. At higher doses, aspirin also reduces synthesis of prostacyclin, another arachidonic acid metabolite. Prostacyclin normally inhibits platelet aggregation. The prophylactic administration of low-dose aspirin has been shown to increase survival following myocardial infarction, decrease incidence of stroke, and assist in maintenance of patency of coronary bypass grafts. 

Ar-(4-ChIorobenzyI)-7-substituted-4-oxo-4//-pyrazino[l,2-tf]pyrimidine-3-carboxarnidcs have been claimed as compounds to treat atherosclerosis and restenosis <2004W02004/019933> and as antiviral agents, particularly against herpes viruses <2002W02002/004444>. The mesoionic pyrazino[l,2-tf]pyrimidine 95 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 

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