Thromboxane analog

The influence of fluorine on the physical, chemical and biological properties of molecules is described. A discussion of the effect of fluorination on bond lengths and bond strengths is presented in the course of an analysis of the steric demand of fluorinated substituents. These steric effects as well as electronic interactions are illustrated in a discussion of fluorinated vitamin D3 and prostaglandin and thromboxane analogs. 

Nicolaou, K., Smith, J. and Lefer, A. (1982). Chemistry and pharmacology of a series of new thromboxane analogs. Drugs Future, 7, 331-340... 

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

Smdies of the stmcture-activity correlations and synthetic modifications of prostaglandins and thromboxane are extremely active fields. Although a large number of analogs have been synthesized, pharmacological information on these analogs is still unfolding. 

The drug most commonly used in patients who do not respond to sildenafil is alprostadil, a PGE1 analog (see Chapter 18 The Eicosanoids Prostaglandins, Thromboxanes, Leukotrienes, Related Compounds) that can be injected directly into the cavernosa or placed in the urethra as a mini suppository, from which it diffuses into the cavemosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil. 

Fluoro prostaglandin, (IV), PGF2a analogs effective as thromboxane A2 receptor agonists were prepared by Klimko (3) and used in the treatment of glaucoma and ocular hypertension. 

For a similar route to a 2-alkoxyoxetane thromboxane A analog combining intermolecular Paterno-BUchi and intramolecular abstraction processes, see H. A. J. Carless and G. K. Fekarurhobo, Tetrahedron Lett., 1985, 26, 4407. 

Lefer AM, Smith 111 EF, Araki H, Smith JB, Aharony D, Claremon DA, Magolda RL, Nicolaou KC. Dissodation of vasoconstrictor and platelet aggregatory activities of thromboxane by carix>cyclic thromboxane Aj, a stable analog of thromboxane Aj. ProcNatl Acad Sci USA 1980 77 1706-10... 

Mais DE, DeHoIl D, Sightler H, Halushka PV. Different j armacologic activities for 13-azapinane thromboxane Aj analogs in platelet and blood vessels Eur J Pharmacol 1988 148 309-15... 

Romstedt KJ, Shin Y, Shams G, Doyle K, Tantisfaaiyakul V, Claric MT, Adqare A, Hamada A, Miller DD, Feller DR. Halogen-substituted trimetoquinol analogs as thromboxane Aj receptor antagonist in platelets and aorta Biochem Pharmacol 1993 46 2051-9... 

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