Thromboxane synthetase receptor antagonists

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. 

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... 

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. 

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],... 

---