. "B1. 1993: RU 486--A Decade on Today and Tomorrow." Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press, 1993.
The following HTML text is provided to enhance online
readability. Many aspects of typography translate only awkwardly to HTML.
Please use the page image
as the authoritative form to ensure accuracy.
Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
"pure" antiglucocorticosteroid(s) that would not display any other endocrine effects.
At present, there is no published account of a pure antiprogestin compound. However, it is important to note that for abortion the antiglucocorticosteroid effect is apparently neither necessary nor even useful, and that a single dose of =600 mg of RU 486 does not create any medical problem related to corticosteroid insufficiency. RU 486 derivatives,* such as RU 46556 and RU 49295, are strong antiprogestins with limited antiglucocorticosteroid activity. ORG 31710 (more active) and ORG 31806 have less antiglucocorticosteroid activity than RU 486 (Mizutani et al., 1992). A 17a-acetoxy derivative such as HRP2000 (Research Triangle Institute, Cook et al., 1992), with a 17ß-progesterone side chain and a 11ß RU 486-like substituent, is both an antiprogestin and an antiglucocorticosteroid. Curiously, 17ß-acetyl, 16a-ethyl derivatives of 11ß-phenyl-substituted steroids are progestin agonists (Cook et al., 1992). The Schering group has synthesized lilopristone, with a 17ß side chain slightly different from that of RU 486; it has less antiglucocorticosteroid activity and higher binding to the androgen receptor. Another compound (ZK 112993) also has reduced antiglucocorticosteroid activity in the rat, due to an acetyl group on the 11ß-phenyl moiety. A significant change in the RU 486 structure was obtained by making onapristone (ZK 98 299); due to photochemical epimerization at C-13, inversion of the D ring and substitutions at the C-17 position occur (Elger et al., 1986; Neef et al., 1984). Onapristone does not bind to orosomucoid (contrary to RU 486), does not bind to the chicken (c) PR (like RU 486) (Nath et al., 1991), is an antiprogesterone (but less active than RU 486), and has weak antiglucocorticosteroid activity. Its mechanism currently is controversial (see later).
A pure antiglucocorticosteroid may be easier to use chronically in premenstrual women. One possibility is RU 40016, an RU 486-like compound with inversion of substituents at the C-17 position. Although not very active, it has relatively more antiglucocorticoid and fewer antiprogestin effects than RU 486. RU 43044 is chemically very different, since the additional phenyl substituent is in the 10ß position, and although this ring is partially superimposable spatially, with a phenyl group in 11ß, there is no binding to the PR, and the activity is purely antiglucocorticosteroid (but weaker than that of RU 486). The compound, perhaps because of its metabolism, has no activity in vivo in animals; however, its activity in situ may provide some clues for the synthesis of a series of locally active thereapeutic agents.
In conclusion, the 11ß-phenyl substitution is essential in determining the antagonistic properties of most antisteroids, while an 11ß-aliphatic
RU 46534 is a very active "contragestive" agent in dogs. The only structural difference with RU 486 is its allylic 17a-side chain.