Antiprogestin mifepristone

Antiprogestins are progesterone receptor antagonists such as mifepristone (RU 38486), ORG 31710, ZK137 316, ZK 230 211, ZK98299 (Onapristone). 

Antiprogestins (eg, mifepristone) have been combined with an oral oxytocic synthetic analog of PGE1 (misoprostol) to produce early abortion. This regimen is available in the USA and Europe (see Chapter 39). The ease of use and the effectiveness of the combination have aroused considerable opposition in some quarters. The major toxicities are cramping pain and diarrhea. The oral and vaginal routes of administration are equally effective, but the vaginal route has been associated with an increased incidence of sepsis, so the oral route is now recommended. 

Other PRMs and pure progesterone antagonists now have been synthesized, and most contain an lip-aromatic group. Another widely studied antiprogestin is onapristone (or ZK 98299), which is similar in structure to mifepristone but contains a methyl substituent in the 13a rather than 13p orientation. More selective PRMs, such as asoprisnil, are being studied experimentally. 

If administered for one or several days in the mid- to late-luteal phase, mifepristone impairs the development of a secretory endometrium and produces menses. PR blockade at this time is the pharmacological equivalent of progesterone withdrawal, and bleeding normally ensues within several days and lasts for 1 to 2 weeks after antiprogestin treatment. 

The antiprogestin, RU 38486 (often referred to as RU-486) or mifepristone, is available for the termination of pregnancy. Antiprogestins have several other potential applications, including uses as contraceptives, to induce labor, and to treat uterine leiomyomas, endometriosis, meningiomas, and breast cancer. 

Mifepristone effectively competes with both progesterone and glucocorticoids for binding to their respective receptors. Mifepristone is considered a PR modulator (PRM) due to its context-dependent antagonist/agonist activity. Another antiprogestin is onapristone, which contains a methyl substituent in the 13a rather than 13 orientation. The structures of mifepristone and onapristone are shown in the 11th edition of the parent text. 

Receptor antagonists of glucocorticoids have been described that are derivatives of 19-nortestosterone (123). Mifepristone, also referred to as RU-486 (Fig. 33.17), was originally developed as an antiprogestin and also exhibits very effective antagonism of glucocorticoids. 

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