Antiprogestins

Agents that specifically block progesterone receptors were first developed in the early 1980s.94 The primary 

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Antiperspirant sticks Antiplasticization Antiprex Antiprogestin Antiprogestins Antiproliferative agents Antiprotozoal... 

In the 1970s and 1980s, potent antiprogestins were discovered and used as contragestational agents, with possible appHcations for the treatment of various cancers. The synthesis of the antiprogestin RU-486 demonstrated a versatile way to functionalize the 11-position of a steroid nucleus. 

Clinical studies with the antiprogestin RU-486 indicate that, when used in a post-coital mode, this dmg may be effective in preventing pregnancy. 

E. E. Bauheu and S. J. Segal eds.. The Antiprogestin Steroid RU486 and Human Fertility Control, Plenum Press, New York, 1985. 

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

In breast cancer patients, total PR status is measured for hormonal treatment. The presence of PR is associated with increased survival rates and hormonal responsiveness of mammary tumors. PR agonists are widely used in contraception, HRT, breast cancer, and endometrial hyperplasia. Antiprogestins such as RU486 are used for blocking ovulation and preventing implantation, and in addition they are in clinical testing for the induction of labor and to control various neoplastic transformations. 

Likewise, the pentafluoroethyl substituent plays an important role in the extraordinarily potent antiprogestin properties of compound 6-3, as well as in the insecticide candidate 6-4 (Fig. 6.2). 

Finally, it has been suggested that fulvestrant, in addition to its antiestrogenic activity, has also significant antiprogestin activity, comparable to the activity of the antiprogestin RU-486 (Nawaz et al. 1999). 

Antiprogestine, substituted at C-17 by a hydroxyl 7-P) and a C2F5 group (17-a), is an antagonist of the progesterone receptor. It is currently in early clinical development. C2F5 is introduced with pentafluoroethyllithium, prepared in s/ fufrom pentafluoroethyl iodide and butyllithium (Fig. 61) [148]. 

After a decrease in the importance of steroids in the field of drug research during the last 20 years, a renewal is now being observed. Recently, some fluorinated and fluoroalkylated steroids have been launched or are in advanced phases of clinical development, such as the dutasteride (5a-reductase inhibitor), CCD-3693 (GABA agonist), fulvestrant and antiprogestine (antihormone), and fluasterone (diabetes) (Figure 4.14). Details on the synthesis on these compounds can be found in Chapter 8. 

Antiprogestine (ZK-230211) is a progesterone receptor antagonist developed for treatment of breast tumors. It is substimted at C-17 by a hydroxyl (17P) and a C2F5 group (17a), which is introduced with pentafluoroethyUithium, prepared in situ from pentafluoroethyl iodide and butyllithium (Figure 8.78). ... 

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. 

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