Prostaglandins thromboxane synthetase

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. 

Uyama O, Nagatsuka K, Nakabayashi S, Isaka Y, Yoneda S, et al. 1985. The effect of a thromboxane synthetase inhibitor, OKY-046, on urinary excretion of immunoreactive thromboxane B2 and 6-keto-prostaglandin El alpha in patients with ischemic cerebrovascular disease. Stroke 16 241-244. 

Figure 16.24 Major prostaglandin and leukotriene products derived from arachidonic acid via the cyclooxygenase and 5-lipooxygenase pathways. Major enzymes 1, cyclooxygenase 2, hydroperoxidase 1 + 2, prostaglandin endoperoxidase synthetase 3, thromboxane synthetase 4, prostacyclin synthetase 5, 5-lipooxygenase 6, 9-ketoisomerase 7, PGH-PGF2a reductase 8, 11-ketoisomerase 9, PGE reductase 10, PGD reductase. (Reproduced by permission from Nelson NA, Kelly RC, Johnson, RA. Prostaglandins and the arachidonic acid cascade. Chem Eng News August 30-44, 1982.)...

Some 1,5-disubstituted imidazoles have been found to exhibit potent inhibitory activity against platelet aggregation and as thromboxane synthetase inhibitors. Hence synthesis of imidazole analogues of prostaglandin require 1,5-orientation. Good yields of these desired isomers are obtained when 4-/-butyldimethylsilyloxymethylimidazole is treated in succession with butyllithium and an... 

Needleman, P., Bryan, B., Wyche, A., Bronson, S.D., Eakin, E., Ferrendelli, J.A. and Minkes, M. (1977). Thromboxane synthetase inhibitors as pharmacological tools Differential biochemical and biological effects on platelet suspension. Prostaglandins, 14, 897-907... 

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... 

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... 

A number of 7 oxabicyclo[2.2.1]heptane prostaglandin analogues were synthesized and evaluated as potential thromboxane synthetase inhibitors or thromboxane antagonists. Several of the compounds tested were shown to be TXA2 antagonists, judged from platelet aggregation and thromboxane inhibition tests. Two of the compounds also inhibited arachidonic acid induced bronchoconstriction [266]. 

We conclude that so far eicosapentaenoic acid has proved to be a very poor substrate for the prostaglandin endoperoxide synthetase (cyclooxygenase + peroxidase) in every species or organ tested, irrespective of whether this enzyme is connected with prostaglandin-, thromboxane- or prostacyclin-biosynthesis. 

The isoxazolidine analogues of the prostaglandin endoperoxide PGH2 have been prepared from PGF2a. Both compounds are potent inhibitors of thromboxane synthetase from human platelets (Scheme 78). ... 

While aspirin significantly inhibits peripheral prostaglandin and thromboxane synthesis, paracetamol is less potent as a synthetase inhibitor than the NSAIDs, except in the brain, and paracetamol has only a weak anti-inflammatory action. It is simple to ascribe the analgesic activity of aspirin to its capacity to inhibit prostaglandin synthesis, with a consequent reduction in inflammatory edema and vasodilatation, since aspirin is most effective in the pain associated with inflammation or injury. However, such a peripheral effect cannot account for the analgesic activity of paracetamol, which is less well understood. 

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