13-azaprostanoic acid

Hu2 or-Akbar, Mukhopadhyay A, Anderson KS, Navran SS, Romstedt K, Miller DD, Fdler DR. Antagonian of prostaglandin-mediated responses in platelets and vascular anooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blodcadeofthromboxane A, responses. Biocfaem Pharmacol 1985 34 641-7... 

Cook, J.A., Wise, W.C. and Halushka, P.V. (1980). Elevated thromboxane levels in the rat during endotoxin shock Protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency. ]. Clin. Invest., 65, 227-230... 

Burke, S.E., Roth, D.M. and Lefer, A.M. (1983). Antagonism of platelet aggregation by 13-azaprostanoic acid in acute myocardial ischemia and sudden death. Thrombosis Res., 29, 473-488... 

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. 

Arachidonic acid, TXA2, PGH2 and their stable mimetics produce an increase in intracellular free calcium in human platelets or alter the binding or flux of calcium in platelet membrane vesicles " ". These effects were blocked by the receptor antagonist, 13-azaprostanoic acid ". The dense tubular system is believed to be the source of calcium. The mechanism by which calcium is elevated in platelets by TXA2/PGH2 or their mimetics remains unknown. However, much recent evidence suggests that turnover of phophatidyl inositol polyphosphates plays an important intermediary role ". ... 

Hung, S.C., Ghali, N.I., Venton, D.L. and LeBreton, G.C. (1983). Specific binding of the thromboxane A antagonist 13-azaprostanoic acid to human platelet membranes. Biochim. Biophys. Acta, 728, 171-178... 

Horn, P., Kohli, J., LeBreton, G. and Venton, D. (1984). Antagonism of prostanoid-induced vascular contraction by 13-azaprostanoic acid (13-APA)./. Cardiovasc. Pharmacol, 6, 609-613... 

Akbar, H., Mukhopadhyay, A., Anderson, K., Navran, S., Ramstedt, K., Miller, D. and Feller, D. (1985). Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Biochem. Pharmacol, 34, 641-647... 

Some of the profound hemodynamic changes seen in endotoxin induced shock, viz. pulmonary hypertension, platelet aggregation and systemic hypotension, have also been correlated with an increased thromboxane biosynthesis [379-384]. Mortality in endotoxic shock was significantly reduced following administration of the thromboxane synthetase inhibitors, imidazole and carboxyheptyl-imidazole, as well as of the thromboxane Aj antagonist, 13-azaprostanoic acid [380,381]. However, the increased PGIj production associated with the systemic arterial hypotension is more likely the cause of the often fatal outcome of this event [384]. 

Venton, D.L., Enke, S.E., and LeBreton, G.C., Azaprostanoic acid derivatives. Inhibitors of arachidonic acid induced platelet aggregation, J. Med. Chem., 11, 824, 1979. 

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