Thromboxane synthetase, inhibition

Shebuski RJ, Storer BL, Fujita T (1988) Effect of thromboxane synthetase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis. Thromb Res 52 381-392 Yasuda T, Gold HK, Fallon JT et al. (1988) Monoclonal antibody against the platelet glycoprotein (GP) Ilb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue type plasminogen activator. J Clin Invest 81 1284-1291... 

Grieve EM, Hawksworth GM, Simpson JG, Whiting PH. Effect of thromboxane synthetase inhibition and angiotensin converting enzyme inhibition on acute cyclosporin A nephrotoxicity. Biochem Pharmacol 1990 40 2323-2329. 

Grieve EM, Hawksworth GM, 5impson JG, Whiting PH.The reversal of experimental cyclosporin A nephrotoxicity by thromboxane synthetase inhibition. Biochem Pharmacol 1993 45 1351-1354. 

FIGURE 14.6 Thromboxane synthetase inhibiting activity of a series of... 

Thromboxane synthetase inhibition is an appealing approach to antithrombotic therapy, since it would be more specific and not shut off the whole AA cascade as do the cyclooxygenase inhibitors such as aspirin. Such a drug should result in an accumulation of PGG2 and PGH2 that could then be diverted to increased prostacyclin production, itself an antithrombotic, thus offering a double-barreled effect. This actually occurs. 

Other examples are symmetrical bradykinine antagonists and symmetrical lexitropsines (netropsine, distamy-cine), active against HIV-I viruses. Non-symmetrical polymethylenic thromboxane synthetase inhibitors are described by Press et al The compounds contain a thiophen-2-carboxamide moiety, separated from an imidazole ring by 3 to 8 methylene units. Surprisingly, whereas most of the compounds show similar thromboxane-synthetase inhibiting activities, only the two medium-sized ones (n = 3 and n —A) showed hypotensive effects in spontaneously hypertensive rats (Fig. 12.6). 

Rg. 12.6 Thromboxane synthetase inhibiting activity of a series of A/- imidazolyl-alkyl)-thiophene-5-carboxa-mide. ... 

Garcia-Szabo, R., Kern, D.F. and Malik, A. B. (1984). Pulmonary vascular response to thrombin Effects of thromboxane synthetase inhibition with OKY-046 and OKY-1581. Prostaglandins, 28, 851-866... 

Burch, R. M., Knapp, D.R. and Halushka, P.V. (1980). Vasopressin-stimulated water flow is decreased by thromboxane synthetase inhibition or antagonism. Am. ]. Physiol, 239, F160-66... 

Klotman, P.E., Smith, S.R., Volpp, B.D., Coffman, T.M. and Yarger, W.E. (1986). Thromboxane synthetase inhibition improves function of hydronephrotic rat kidneys. Am. ]. Physiol, 250, F282-F287... 

Mogensen, K., Knudsen, J.B., Rasmussen, V., Kjoiler, E. and Gormsen, J. (1985). Effect of specific thromboxane synthetase inhibition on thromboxane and prostaglandin synthesis in stable angina induced by exercise test. Thrombosis Res., 37, 259-266... 

Some stable thromboxane A2 analogues with thromboxane synthetase inhibiting properties have also been synthesized [154-156], but these compounds exhibited agonistic or antagonistic properties as well (see below). 

---