B1
1993: RU 486—A Decade on Today and Tomorrow

Étienne-Émile Baulieu, M.D., Ph.D.

Unité de Recherches sur les Communications Hormonales (INSERM U 33) and Faculté de Médecine Paris-Sud, Bicêtre Cedex, France

The development of RU 4861 (Figure B1.1), the first efficient antiprogestin, may be seen as a result both of the biomedical revolution of the last few decades and the efforts of the women's movement during the twentieth century to control their reproductive life. This conjunction was exemplified in the early 1950s when Margaret Sanger went to Gregory Pincus to discuss the possibility of developing a medical method to achieve "planned parenthood." The result of this meeting, which merged science (hormone research) and the cause des femmes, was the invention of the contraceptive pill (Pincus, 1965). "The pill" remains at least as important symbolically as it is useful practically. Scientifically, this development was based on the physiological concept that sex steroid hormones exert negative feedback control on ovulation. With progress in steroid chemistry, orally active compounds that mimicked the action of endogenous steroids were developed (Djerassi, 1970).

In the 1960s and 1970s, it became clear that the available contraceptive methods did not completely meet the needs of women and their families; nor would they alone have a sufficient demographic impact to

1  

Mifepristone (RU 38486): 17ß-hydroxy-11ß-(4-dimethylaminophenyl-1)-17a (prop-1-ynyl)-estra-4,9-dien-3-one. Many publications are already available for reference: Herrmann et al. (1982) presented the first laboratory and clinical data on RU 486; the book edited with S. Segal (Baulieu and Segal, 1985) reported on the Bellagio meeting, which grouped almost all contributors known at that time; and many other reviews have partially covered the field, which has become very large: Henderson (1987); Neef (1987); Baulieu (1989a,b, 1991a,b); Laue et al. (1989); Avrech et al. (1991); Philibert et al. (1991); Ulmann et al. (1990); Cook and Grimes (1992); Horwitz (1992); Mao et al. (1992); Brodgen et al. (1993).



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda B1 1993: RU 486—A Decade on Today and Tomorrow Étienne-Émile Baulieu, M.D., Ph.D. Unité de Recherches sur les Communications Hormonales (INSERM U 33) and Faculté de Médecine Paris-Sud, Bicêtre Cedex, France The development of RU 4861 (Figure B1.1), the first efficient antiprogestin, may be seen as a result both of the biomedical revolution of the last few decades and the efforts of the women's movement during the twentieth century to control their reproductive life. This conjunction was exemplified in the early 1950s when Margaret Sanger went to Gregory Pincus to discuss the possibility of developing a medical method to achieve "planned parenthood." The result of this meeting, which merged science (hormone research) and the cause des femmes, was the invention of the contraceptive pill (Pincus, 1965). "The pill" remains at least as important symbolically as it is useful practically. Scientifically, this development was based on the physiological concept that sex steroid hormones exert negative feedback control on ovulation. With progress in steroid chemistry, orally active compounds that mimicked the action of endogenous steroids were developed (Djerassi, 1970). In the 1960s and 1970s, it became clear that the available contraceptive methods did not completely meet the needs of women and their families; nor would they alone have a sufficient demographic impact to 1   Mifepristone (RU 38486): 17ß-hydroxy-11ß-(4-dimethylaminophenyl-1)-17a (prop-1-ynyl)-estra-4,9-dien-3-one. Many publications are already available for reference: Herrmann et al. (1982) presented the first laboratory and clinical data on RU 486; the book edited with S. Segal (Baulieu and Segal, 1985) reported on the Bellagio meeting, which grouped almost all contributors known at that time; and many other reviews have partially covered the field, which has become very large: Henderson (1987); Neef (1987); Baulieu (1989a,b, 1991a,b); Laue et al. (1989); Avrech et al. (1991); Philibert et al. (1991); Ulmann et al. (1990); Cook and Grimes (1992); Horwitz (1992); Mao et al. (1992); Brodgen et al. (1993).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.1 Mifepristone (RU 486). limit the population explosion. During those decades, ideas for new methods of contraception emerged as biology became focused more on the cellular and molecular elements of regulation of the reproductive system. The hormone-responsive proteins of target cells in the reproductive tract (termed receptors) were discovered, while progesterone (P), designated as the hormone of gestation (pro gestare) by Corner (in 1932) (Corner, 1963), was now easy to quantitate by radioimmunoassays (Lieberman et al., 1959). The uterine progesterone receptor (PR) (Milgrom et al., 1970) and the synthesis and action of prostaglandins (PG) (Bergström et al., 1972) were described, while the role of progesterone in the establishment and maintenance of pregnancy in women was demonstrated (Csapo and Pulkkinen, 1977). As it became clear that progesterone is involved at all steps of the reproductive processes, antagonists of progesterone were actively sought. As early as 1975, the concept of a "midcycle" contraceptive, a method based on progesterone receptor down-regulation with an "antiprogesterone" ligand, was proposed (Baulieu, 1975). Now, in 1993, we have a number of efficient antiprogestins. Although induction of abortion has been the most immediate application of such compounds, other potential applications include delivery, contraception, and treatment of several hormone-dependent diseases. When developing a procedure for the termination of pregnancy in women, it is important to be aware of both moral and physiological ideals, as well as psychological concerns. For centuries, abortion has been not only a morally difficult event for women, but also a physically painful and often dangerous procedure. A medical means for pregnancy termination should diminish this threat to women's health and, in turn, allow them to maintain their dignity. Furthermore, the distinction between abortion and contraception has lessened because the beginning of pregnancy is now understood, in physiological terms, to be a progression of steps. Hence, the term "contragestion" was proposed (Baulieu, 1985, 1989a, b) to clearly designate a method that can provoke pregnancy interruption (contra gestation) and operates as soon as possible after fertilization might have occurred, before the word abortion is appropriate (is an IUD considered an abortifacient?, see later discussion). This change in concept may be one of the most important outcomes of RU 486 development and usage.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda ANTIHORMONES: THE 20 YEARS BEFORE RU 486 The aim of suppressing hormone activity is almost as old as the word hormone (wrm‘‘’ein: to excite) itself. If a hormone molecule is excitatory for the target cells, then suppression of its effects can be attained by (1) abolition of its production, (2) blockade of its transport from the gland that produces it to target organs, or (3) blockade of its action at the target cell. In the case of small, lipophilic steroids such as P, which act intracellularly, the latter possibility could mean prevention of its entry into potentially responsive cells. The first of these possibilities, suppression of biosynthesis, seems feasible in humans for some situations. For example, enzymatic inhibitors such as Epostane (4,5-epoxy-17ß-hydroxy-4, 17a-dimethyl-3-oxo-5a-androstane-2-carbonitrile), which inhibits 3ß-hydroxysteroid dehydrogenase, have been tested with some success in abortion (Birgerson and Odlind, 1987; Crooij and Janssens, 1988). An approach that blocks the action of hormones using specific antihormone antibodies—such as antibodies that interact with P in the blood or in target organs (Wang et al., 1989)—does not seem easily applicable to humans. However, an antihormone that operates directly at the receptor level may act more rapidly and be more specific than an inhibitor of a key enzyme involved in the synthesis of many steroids. In fact, the center of hormone action and thus the best molecular target for antihormonal action is the receptor (R) protein molecule, a mandatory element for cellular responses to hormone.2 The image of a receptor portrayed as a lock whose key is the hormone and whose keyhole (in fact a "binding site") can be competitively occupied and consequently put out of order by a false key (an antihormone) has been popular for decades. Because steroids are rigid molecules of well-defined conformation, as the high-affinity binding site of the receptor should be, it seemed logical to expect that a breakthrough in the hormone antagonism field would occur first in the antisteroid field. Initially, steroid receptors were detected by the binding of a traceable (radiolabeled) hormone to tissue extracts. The first of these so-called "radioreceptor" experiments was performed with tritiated estradiol (the natural estrogen) and MER 25, an antiestrogen (Segal and Nelson, 1958) that competed efficiently for radioactive hormone uptake and retention in the uterus (Jensen and Jacobson, 1962). The structure of MER 25 (Figure B1.2) is not that of a steroid. It is a triphenylethylene stilbene derivative with two phenyl rings mimicking rings A and D of 2   RU 486 can be accommodated between partially unwound, double-stranded DNA bases by computer modeling. Yet the altered conformation of DNA cannot be correlated with the pharmacological properties of antiprogestins (Hendry and Mahesh, 1992).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.2 Structure of some progestins, estrogen agonists, and antagonists. the steroids. X-ray crystallographic studies of the nonsteroidal estrogen diethylstilbestrol (DES) and estradiol (E) have delineated their similarity (Hospital et al., 1972). The third ring of triphenylethylene derivatives is perpendicular to the rest of the steroid-mimicking skeleton (Figures B1.2 and B1.3)—a fact that was of great importance. Given the high affinity that molecules such as E and DES show for the receptor, it was not surprising that triphenylethylene derivatives such as MER 25 and tamoxifen (Figure B1.2) had lower affinity than the agonists. However, the presence or absence of the third phenyl ring is not the critical factor for determining binding affinity since 4-hydroxytamoxifen, with an additional hydroxyl on the ring A equivalent of the tamoxifen molecule, mimicking the 3-hydroxyl group of estradiol, is a compound with high affinity for the receptor and has a resulting strong antiestrogenic effect ("pure" antagonist with no agonist activity in the chick) (Sutherland et al., 1977).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.3 Superimposition of RU 486 and tamoxifen skeletons. Calculations from X-ray crystallographic data were made by Jean-Paul Mornon (Laboratoire de Crystallographie, CNRS URA 09 and Universités Paris VI and Paris VII). I was very impressed by these last data concerning 4-hydroxytamoxifen because they contradicted the thinking of the time—all known antagonists had low affinity for their respective receptors: antiestrogens (e.g., tamoxifen), antiandrogens (e.g., cyproterone acetate, flutamid), antiglucocorticosteroids (e.g., P), and antialdosterone (e.g., spironolactone, P). Screening for antihormonal steroids tended to eliminate compounds demonstrating a high affinity for the receptor. In fact, there was no adequate theoretical reason to equate the quantitative notion of high affinity with the qualitative property of hormone antagonism. The latter was predictably due to specific conformational changes of receptor domain(s) that are involved in the transcription activation functions (TAF) of the receptor (see Figure B1.7 and later discussion), in particular in the ligand binding domain (LBD). In contrast, steroid binding affinity reflects interaction with the binding site, also located in the LBD, and is important only for kinetic quantitative aspects of the antihormone activity. I presented this scenario to Robert Bucourt who was head of chemistry at Roussel-Uclaf in the early 1970s. Interestingly, Dr. Bucourt and his colleagues had collaborated with us to purify the estrogen receptor by affinity chromatography. Initially, this involved the screening of potential receptor ligands. Among the synthetic derivatives tested by Hélène Richard-Foy were estrogens with a long side chain grafted at the 7a-position. We selected one of them for receptor purification (Bucourt et al., 1978); however, Roussel did not test its biological activity. [About 10 years later, it was found to be an antagonist of estrogens by ICI researchers (Wakeling and Bowler, 1988).] It is important to note that the 7a-substitution on the steroid skeleton is somewhat symmetrical to an 11ß-substitution, consistent with the

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda structures of the triphenylethylene antiestrogens and of the 11ß-phenyl derivative compounds of the RU 486 series. Also in the early 1970s, the Roussel chemists were working to improve the synthesis of new glucocorticosteroids and found a new way to produce 11ß-derivatives of steroids. They discovered that 5a, 10a-epoxides obtained by metachloroperbenzoic acid treatment of 5(10), 9(11)-estradienes are prone to nucleophilic opening with Grignard reagents (Nédélec and Gasc, 1970). In addition, either copper chloride-catalyzed Grignard reagents or lithium organocuprates efficiently gave the corresponding regio- and stereospecific 11ß-substituted 4,9-estradienes (Teutsch and Bélanger, 1979; Bélanger et al., 1981). Interestingly, the size of the substituent appears to largely determine agonistic or antagonistic activities. Thus chemical research on the synthesis of glucocorticosteroids and biological studies of estrogens/antiestrogens converged when the RU 486 series of compounds was synthesized by Georges Teutsch and colleagues (Teutsch et al., 1988). The remarkable analogy of orientation of the third ring of tamoxifen and the fifth ring of RU 486 (approximately coplanar with the C-9 to C-11 bond, both perpendicular to the basic stilbene or steroid skeletons), is shown in Figure B1.3. Indeed, the 11ß-phenyl-N-dimethyl-substituted estradiol is a strong antiestrogen (unpublished result). The rest of the RU 486 story, which has been presented in several publications (see footnote 1), continued with the observation of the antiglucocorticosteroid activity of RU 486, and thereafter the demonstration of its antiprogesterone property. The decision to test it for human abortion was made after the endocrinological and pharmacological studies performed by Daniel Philibert and colleagues. We proposed that the compound was active and probably safe, but the idea of using RU 486 in human beings was almost ''killed" by toxicologists who did not correctly interpret the signs of cortisol insufficiency when the product was given at very high doses in monkeys for several consecutive weeks. RU 486 was rescued by my insistence that it was just a beautiful (in vivo) demonstration of the antiglucocorticoid activity of the compound in primates (Baulieu, 1991c). This compound became the subject of a political debate that is not relevant to this review. However, the scientific story is not complete, and should be pursued in order to improve and to extend the first discoveries. CHEMISTRY: NOVEL MOLECULES Almost all the potent antiprogestins and antiglucocorticosteroids so far described are 11ß-phenyl-substituted steroids. The exception is RU 43044 (Figure B1.4), a 17ß-substituted steroid: see later in the text. The

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.4 Structure of some currently available progestins and antiprogestins. relatively long half-life of RU 486 in human beings (˜20 hours) seems to be due to its ability to bind to plasma orosomucoid (an a1-glycoprotein) (Moguilewski and Philibert, 1985; Grimaldi et al., 1992). This binding is not found in nonhuman primates or other animals. RU 40555 (see Figure B1.4 for structure of this and other compounds discussed in this section) does not bind to the orosomucoid and has a shorter half-life, which may be of interest for kinetic assessment of the hypothalamus-pituitary-adrenal axis in clinical endocrinology (Bertagna et al., 1984; Gaillard et al., 1984). However, the binding of RU 486 and lilopristone (ZK 98734) to orosomucoid may enhance the antisteroid activity since it protects the drug against metabolic inactivation and provides a reservoir system for sustained delivery to target cells. Since the early studies with RU 486, chemists have tried to dissociate the two main antihormonal activities of the compound and have aimed, for obvious medical reasons, to obtain "pure" antiprogestin(s) and

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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.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.5 Agonists and antagonists of 11β-substituted steroids. Agonistic and antagonistic potential of two series of 11β-substituted steroids that differ from RU 486 only in their 11β-substitutions or their 11β- and 17α-substitutions. The chemical symbols in the top right corner of the upper panels illustrate the 17α-substitutions. Transcription activation was quantitated from normalized CAT assays in HeLa transiently-transfected cells with the MMTV-CAT reporter gene and the human progesterone-receptor (hPR) expression vector hPR1 in the presence of the various compounds. The agonistic potential of the hPR in the presence of 1 µM of these steroids alone (- RU 27987, at the top) is expressed as a positive value relative to the activation seen with 10 nM RU 27987 (arbitrarily assigned +100). Antagonistic potential was assayed by exposing transfected cells to 1 µM of a given steroid plus 10 nM RU 27987 (+ RU 27987 at the top) and is expressed as a negative value, with -100 indicating complete inhibition of RU 27987-induced transcription. The individual 11β-substitutions are depicted. RU 27987 is a 17α,21-dimethyl-3,20-dioxo-21-hydroxy-19-nor-pregna-4,9-diene progestin agonist. SOURCE: Garcia et al. (1992); © The Endocrine Society. chain may result in agonistic derivatives (Figure B1.5). However, most steroidal structures do not carry an absolute intrinsic property of agonism or antagonism per se, as demonstrated by steroid binding differences between the PR of different species, changes of activity when mutating the receptor LBD, and activity differences in various target cells under different physiological states. RU 486 and many corresponding compounds from Schering and Organon do not bind to cPR (Groyer et al., 1985), although they bind to the PR of humans (hPR) and most other mammals. The change of a cysteine (Cys) in the N-terminal region of the cPR LBD (Cys 575) to a glycine (Gly), as found in the hPR (cPR Cys 575 → Gly), permits the binding of RU 486 and antisteroid activity. Interestingly, RU 39115 (which is RU 486 minus N-dimethyl) is an antagonist of the hPR, but an agonist of the "humanized" chicken PR (cPR 575 → Gly). This indicates that the interaction of steroid and receptor is more complex than just binding

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.6 Agonists, antagonists, and mixed agonists-antagonists. Ligands for the hPR may generate three distinct types of TAF2-dependent transcriptional responses: they act as agonists with no antagonistic potential or as antagonists with no agonistic potential, or they may generate a mixed response, since they both activate and antagonize transcription activation. HeLa cells were transiently transfected with a reporter gene and a progesterone response element and exposed to the steroids in the absence or presence of RU 27987 (Figure B1.5). Steroids were used at 1 µM (- RU 27987; lanes 3, 5, 7); in cases where the antagonistic potential was analyzed, activation was achieved with 10 nM (RU 27987; lanes 4, 6, 8). Note that RU 28289 acts as both agonist and antagonist. SOURCE: Garcia et al. (1992); © The Endocrine Society. ability, and may depend on the overall structure of the LBD and consequent modification of TAF2 function (see later). Systematic experiments indicate that depending on the nature and positioning of the 11ß-phenyl substituent, one may produce 11ß-substituted steroids with progestin agonistic, antagonistic, or mixed agonistic and antagonistic activities (with, as expected, no relationship to binding affinity) (Benhamou, 1992; Garcia et al., 1992) (Figure B1.6). Indeed it is logical that the structure of the steroids and of the LBD combine ultimately to direct the conformation and, thus, the function of TAF2, therefore "deciding" if a compound will act as an agonist or an

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda FIGURE B1.7 Schematic representation of a steroid hormone-receptor consensus structure in its "8S" heterooligomeric form. NOTE: aa = amino acid; NLS(c) = constitutive nuclear localization signal; NLS(hd) = hormone-dependent nuclear localization signal; Di = dimerization; FK = FK506; CAM = calmodulin; C = cysteine; + and - = conserved charged amino acids. Other abbreviations are as indicated in text. antagonist. This is potentially important for cancer treatment, since the steroid-receptor mutations that are observed in certain tumors may radically change the properties of their receptors and the effectiveness of steroidal drugs. CELLULAR AND MOLECULAR MECHANISMS OF ACTION OF ANTIPROGESTINS: THE RECEPTOR AT THE CENTER The "consensus" anatomy of steroid receptors (Evans, 1988) and the concept of associated proteins (Lebeau et al., 1993) are illustrated in Figure B1.7. Shown in Table B1.1 and Figure B1.8 are several steps involved in the intracellular mechanism of steroid hormone and antihormone action. Progesterone, cortisol, and their cognate synthetic agonists and antagonists seem to enter target cells freely and appear not to be

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