Thromboxane synthase inhibitors

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... 

Tozaki H, Fujita T, Odoriba T, et al. Colon specific delivery of R 68070, a new thromboxane synthase inhibitor using chitosan capsules therapeutic effects against 2,4,6-trinitrobenzene sulphonic acid-induced ulcerative colitis in rats. Life Sci 1999 64 1155-1162. 

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. 

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). 

Chouinard ML, Martin LL, Coffman T, Hamilton BH, Linberg LF, Pamidi A, Simke JP, Rakhit A. Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients. Clin Pharmacol Ther 1992 52 597-604. 

Weir MR, Klassen DK, Burdick JR A pilot study to assess the ability of an orally available selective thromboxane synthase inhibitor to improve renal function in cyclosporine-treated renal transplant recipients. J Am Soc Nephrol 1992 2 1285-1290. 

Thromboxane synthase inhibitors have been a matter of interest for many years because of their potential use in preventing plugs of platelets, and efforts at development preceded the characterization of the enzyme as a P450 (refs [1008-1010]). Many of these inhibitors have a basic nitrogen atom that binds to the P450 5A1 heme ". The... 

Hecker, M., M. Haurand, V Ullrich, and S. Terao (1986). Spectral studies on structure-activity relationships of thromboxane synthase inhibitors. Ear. J. Biochem. 157, 217-223. 

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. 

Figure 6.1 Proposed mechanisms of action of thromboxane synthase inhibitors on platelet activity. Thromboxane synthase inhibition prevents the conversion of prostaglandin endoperoxides (PGH2) to thromboxane A2 (1). Prostaglandin endoperoxides are proaggregatory (2) and are metabolized by endothelium to platelet-inhibitory prostacyclin (3)...

Whether endogenous prostacyclin modulates platelet activity in vivo is uncertain, but studies using cyclo-oxygenase and thromboxane synthase inhibitors in animal models of thrombosis support this hypothesis. Inhibition of platelet deposition on de-endothelialized rabbit abdominal aorta by aspirin is dose dependent, being less at higher doses at which coincident inhibition... 

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