Thromboxane synthetase receptor

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. 

Apprill P, Schmitz JM, Campbell WB et al. (1985) Cyclic blood flow variations induced by platelet-activating factor in stenosed canine coronary arteries despite inhibition of thromboxane synthetase, serotonin receptors, and a-adrenergic receptors. Circulation 72 397-405... 

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... 

Heinisch, G., Holzer, W., Kunz, F., Langer, T., Lukavsky, P, Pechlaner, C., Weissenberger, H. On the bioisosteric potential of diazines diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor ridogrel. 7. Med. Chem. 1996, 59(20), 4058-4064. 

Soyka, R., Heckel, A., Nickl, J., Eisert, W., Muller, T. H., Weisenberger, H. 6,6-Disubstituted hex-5-enoic add derivatives as combined thromboxane A2 receptor antagonists and synthetase inhibitors. J. Med. Chem. 1994, 37, 26-39. 

Effect of thromboxane synthetase inhibitors and receptor antagonists... 

The third reason was that, shortly after the discovery of TxA2, it was postulated that it could act as a calcium ionophore. It was speculated that TxA2 could translocate Ca " from its storage site within platelets to the cytosol. This event could be envisioned to occur without a receptor. This notion was dismissed, however, with the discovery of 13-azaprostanoic acid °, the first TXA2/PGH2 receptor antagonist, which had no effect on thromboxane synthetase. 

A more active thromboxane receptor agonist was found in the 9a-homo-9,l 1-epoxy-5,13-prostadienoic acid analogue, SQ 26,538. This compound was 200 times more potent than arachidonic acid in inducing platelet aggregation but was onl> 1/10 as potent as PGH2. This effect was not blocked by inhibitors of cyclo-oxygenas< or of thromboxane synthetase [241]. 

The compound [ la(Z),2, 5a]-methyl-7-[2-(4-morpholinyl)-3-oxo-5-(phenyl-methoxy)cyclopentyl]-5-heptenoate (AH 19437) inhibited platelet aggregation and 5-hydroxytryptamine release without inhibiting fatty acid cyclo-oxygenase, thromboxane synthetase, cAMP phosphodiesterase or prostacyclin synthetase, consistent with the view that AH 19437 is a selective antagonist of platelet TXAj receptors [254-256],... 

Figure 1 Representative pharmacophore queries (a) simple thromboxane synthetase inhibitor, (b) CNS agent, and (c) optimized receptor-based ACE inhibitor query derived from bound inhibitor of carboxypeptidase A...

Two other publications on the bioisosteric replacement of pyridine show similar results. The first paper reports the study of bioisosteric potential of diazines in the field of combined antithrombic thromboxane A2 synthetase inhibitors and receptor antagonists. On the basis of the structure-activity relationships (SAR) observed in this study, it turned out that only the 2-pyrazinyl, 4-pyridazinyl... 

The adversary relationship between prostacyclin (PGI2) and thromboxane-A2 (TXA2), which modulates coronary blood vessel caliber [112] and platelet aggregation [113], presents opportunities for therapeutic intervention in cardiovascular diseases. Substances that inhibit TXA2 synthetase or interfere at the TXA2 receptor... 

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