Discovery thromboxanes

Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prostaglandin El, F2, A2, etc.), with their powerful associated activities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the non-... 

Lipids have multiple roles in cells. Recent discoveries show that the same lipid may have both structural and regulatory roles in the cell. For example, while arachidonic acid (20 4co6) is a major constituent of brain inositides and PtdEtn, the free acid is also a precursor of a number of important bio messengers, the eicosanoids, such as prostaglandins, prostacyclins, leukotrienes and thromboxanes... 

The biological properties of oxetanes are slowly attracting attention, although many have been known for a long time. For example, 2,2-bis(p-ethoxyphenyl)-3,3-dimethyloxetane is an excellent insecticide, 25 times as potent as DDT (71MI51300). Many oxetanes have been patented as fungicides. The recent discovery of thromboxane A2 and the antileukemic toxanes will undoubtedly stimulate further study of oxetane derivatives for possible medical and biological applications. 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-ep/-PGF2[J that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome. 

Kyowa Hakko Kogyo Co.) anti-inflammatory thromboxane synthetase inhibitor "discovery ... 

Fig. 5.3) (274). The multiple activities of these substances were the topic of intense research in the 1960s and 1970s, where roles in reproductive, cardiovascular, pulmonary and renal physiology, and pathophysiology (pain, inflammation, cancer) -were identified. The discovery of thromboxane (275) and prostacyclin (276) came later and expanded the role of the eicosanoids as powerful substances in human physiology. 

Elaboration of the discovery that 15-hydroperoxy-AA inhibits PGI2 synthetase s has revealed that 12-hydroperoxy-AA inhibits thromboxane synthetase, while u)-8 and 03-10 hydroperoxides of linoleic, dihomo-y-linolenic and AA inhibit prostacyclin synthetase.It seems possible that these hydroperoxides may perform a negative feedback role to inhibit excess thromboxane or PGI2 formation. The effects of the 5-hydroperoxy-AA formed by rabbit polymorphonuclear leucocytes have not been investigated. 

Samuelsson, B. An elucidation of the arachidonic acid cascade. Discovery of prostaglandins, thromboxane and leukotrienes. Drugs 1987, 55(Suppl. 1), 2-9. 

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 discovery of the thromboxanes, and especially subsequent studies on the metabolism of TXBj, made it necessary to introduce a nomenclature for the thromboxanes [22], The basis for the nomenclature is the parent compound throm-bane and corresponds to that in prostaglandin nomenclature [23] with the exception of the oxane oxygen which is designated 11a (Fig. 3). 

As mentioned above, TXA was also found to be a potent contractile agent in airways [21]. This effect is demonstrable both in vitro and in vivo, and this discovery together with other findings led to the hypothesis that TXA2 might be a mediator of broncho-constriction in asthma. The possible roles of the thromboxanes in the respiratory system, as well as their interactions with the even more potent leukotrienes, are discussed more in detail below (see Thromboxanes and the lung). 

Shortly after the discovery of the thromboxane pathway, reports began to appear describing different agents with inhibitory effect on thromboxane synthetase. 

The discovery of the prostaglandin endoperoxides and thromboxane Aj, compounds with pronounced biological activity but short half-life under physiological conditions, initiated a search for stable synthetic compounds that mimic the actions of the labile arachidonate metabolites. Several of these synthetic compounds are structural analogues to PGH2. 

Ever since the discovery of TXA2, much effort has been directed towards the search for compounds that either inhibit its formation or antagonize its actions, since TXA2 has been postulated to be involved in a number of pathophysiological conditions. Some of the compounds that have been described as antagonists of thromboxane action are reviewed below. 

However, after the discovery of the antagonistic prostacyclin [349,350], formed in the vessel wall from the same precursor as thromboxane, an explanation for this discrepancy was obtained. Obviously, the biosynthesis of this anti-aggregatory vasodilating substance is also inhibited after ingestion of aspirin, and thus the net effect of such a treatment is negligible. 

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