Thromboxane receptor inhibitors

Drugs that target other sites of platelet action include thromboxane synthetase inhibitors, serotonin or 5-hydroxytryptamine (5-HT2) receptor blockers, and thromboxane A2 receptor blockers, in addition to cyclooxygenase inhibitors and prostaglandin analogues. 

The development of selective thromboxane synthase inhibitors and TXA2 receptor antagonists has required considerable effort. The resulting compounds, eg, sulotroban, have been useful for characterizing TXA2-related effects in vitro and in vivo. They are being tested in the treatment of thromboembolism, pulmonary hypertension, and preeclampsia-eclampsia. 

Hoet B, Amout J, Van Geet C, Deckmyn H, Verha e R, Vermylen J. Ridogrd, a cnnbined thromboxane synthase inhibitor and receptor blocker, decreases elevated plasma p-thrombc>globulin levds in patients with documented peripheral arterial disease. Thromb Haemost 1990 64 87-90... 

Gresele P, Dedomyn H, Amout J, N nci GG, V rmyl n J. Characterization of N,N -t>is(3 pioolyl)-4-methoxy-isophthalamide (piootamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. HircmibHaemost 1989 61 479-84... 

Gresek. P. era/. (1991) Thromboxane synthase inhibitors, thromboxane receptor antagonists and dual blockers in thrombotic disorders. Trends Pharmacol Sci., 12.158-163. 

Fujita, M., Seki, T., Inada, H., Shimizu, K., Takahama, A., Sano, T. Approach to dual-acting platelet activating factor (PAF) receptor antagonist/thromboxane synthase inhibitor (TxSl) based on the link of PAF antagonists and TxSls. Bioorg. Med. Chem. Lett. 2002, 12, 341-344. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

Finally, the investigational use of new pharmacotherapeutics such as thromboxane synthase inhibitors, vasodilator prostaglandin infusions, antioxidants, and P-receptor agonists in the treatment of microvascular permeability edema is well covered in several reviews (Demling, 1982 McMillan and Boyd, 1982 Persson et al., 1982). 

As well as the apparent pathological role that thromboxane A2 plays in unstable angina, it also seems to be involved in the transient ischaemic attacks that occur in stroke patients. Aspirin is recommended by the FDA for treating these patients. The evaluation of thromboxane synthase inhibitors and prostaglandin endoperoxide-thromboxane A2 receptor antagonists in the clinical setting will doubtless reveal pathological roles for thromboxane A2 in other human diseases. 

Effect of thromboxane synthetase inhibitors and receptor antagonists... 

Figure 6.5 Percent change in thromboxane A2 and prostacyclin biosynthesis, measured as excretion of their urinary metabolites, 2,3-dinor-thromboxane (Tx) 82 and 2,3-dinor-6-keto-prostaglandin (PG) respectively, in response to a thromboxane A2/prostaglandin endoperoxide receptor antagonist (L636,499) alone and in combination with a thromboxane synthase inhibitor (U63,557A) in the chronic canine model of coronary thrombosis. (Note that occlusion did not occur in dogs treated with the combination therapy)...

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