Antagonist, progesterone

The synthesis of the first of these antagonists, mifepristone (28-3), starts by conversion of the intermediate (24-2) to the corresponding 3,17 diketone by sequential saponfication of the benzoate at 17 and oxidation of the resulting alcohol. Reaction of the compound with ethylene glycol proceeds preferentially at the 3 position to 

A recent compound in this class, asoprinosil (29-9), is a more selective antagonist of progesterone and also shows reduced binding to glucocorticoid receptors. Treatment of the diene (29-1), a total-synthesis product-derived 19-nor gonane, with hydrogen peroxide results in selective reaction at the 5,10 double bond to 

The synthesis of the progestin antagonist onapristone (31-2) also starts with the saponification product from (24-2). In this case, the intermediate is first converted to a 3,3-drmethylpropylene acetal by reaction with neopentyl glycol oxidation as 

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Edwards DP, Altaman M, DeMarzo A, Zhang Y, Weigel N, Beck CA (1995) Progesterone receptor and the mechanism of action of progesterone antagonists. J Steroid Biochem Mol Biol 53 449... 

Olive DL (2002) Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 57 S55-63... 

Spitz IM (2003) Progesterone antagonists and progesterone receptor modulators an overview. Steroids 68 981-993... 

Jonat W, Giurescu M, Robertson JFR (2002) The Clinical Efficacy of Progesterone Antagonists in Breast Cancer. In Robertson JFR, Nicholson Rl, Hayes DF (eds) Endocrine Management of Breast Cancer. Martin Dunitz Ltd, London... 

B. RU 486 acts as a competitive progesterone antagonist and blocks progesterone binding at its receptors. It has no activity at estrogenic receptors. 

The C-17 acetylenic progesterone antagonist (nore-thyndrone) is also an enzyme activated inhibitor of the aromatase. 

Maria B, Stampf F, Goepp A, Ulmann A. Termination of early pregnancy by a single dose of mifepristone (RU 486), a progesterone antagonist. Eur J Obstet Gynecol Reprod Biol 1988 28(3) 249-55. 

Ottow, E. Neef, G. Wiechert, R. Stereo- and regiospedfic 6-endo-trig-cyclization of aryl radicals, an entry to novel progesterone antagonists of the androstane series. Angew. Chem. Int. Ed. 1989, 28, 773-776. 

Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-IA). Nat Med 9 1533-1537... 

Leonhardt SA, Edwards DP. Mechanism of action of progesterone antagonists. Exp. Biol. Med. 2002 227 969-980. 

Even more controversial is the progesterone antagonist mifepristone (RU-486). This drug taken during the first 49 days of pregnancy causes the embryo to be aborted. Because it induces abortion, mifepristone has generated considerable protest, but it is in widespread use in Europe and has been approved in the United States (Hyde DeLamater, 2006). 

Klijn, J.G., Setyono Han, B. and Foekens, J.A. (2000) Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids, 65, 825-830. 

Slayden, O.D., Chwalisz, K. and Brenner, R.M. (2001) Reversible suppression of menstruation with progesterone antagonists in rhesus macaques. Human Reproduction, 16, 1562—1574. 

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