Selective progesterone receptor modulator

Last updated
Selective progesterone receptor modulator
Drug class
Ulipristal acetate skeletal.svg
Ulipristal acetate, an SPRM that is used as an emergency contraceptive and in the treatment of uterine fibroids.
Class identifiers
Synonyms SPRM
Use Emergency contraception, uterine fibroids
ATC code G03XB
Biological target Progesterone receptor
Chemical class Steroidal
Legal status
In Wikidata

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists (e.g., progesterone, progestins) and full antagonists (e.g., aglepristone) is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates. [1]

Contents

History

Ever since the discovery of the progesterone hormone in the mid-1930s. [2] [3] and especially after the discovery of its receptor in 1970 [4] [5] there has been a significant interest in developing an antagonistic agent for therapeutic use. Various progesterone analogs, known as progestins, were synthesized and in 1981 the first progesterone receptor antagonist was introduced by the name RU 38486 (RU 486, mifepristone). [6] [7] However, the clinical limitation of mifepristone due to its relatively high binding affinity for glucocorticoid receptor compared to the progesterone receptor has sparked the demand for more selective progesterone antagonist to minimize risk of adverse effects. [7] [8] [9] As a contribution, so-called Selective Progesterone Receptor Modulators (SPRMs) have been developed. They have been described as agents with mixed antagonistic and agonistic effects on progesterone receptors in a tissue specific manner, while minimizing interactions with other steroidal receptors. [10] [11] Opposed to progesterone antagonists, the mixed agonist-antagonist SPRM, due to their intrinsic progesterone agonistic activity, have an absent or only a minimal effect on pregnancy termination and are thus ideal for treating gynecological conditions without eliminating the potential of pregnancy. [12] Both steroidal [13] and non steroidal SPRMs [14] have been described and the most notable examples are asoprisnil, [15] which failed phase 3 clinical trial in 2008, [16] and ulipristal acetate, [17] the first SPRM on the market (2009 in Europe [18] ).

Progesterone receptor

Receptor

Figure 1: Progesterone Receptor Protein PGR PDB 1a28.png
Figure 1: Progesterone Receptor

As a protein, the progesterone receptor (Fig. 1) is a member of the ligand-dependent nuclear hormone receptor family. [19] Two major progesterone receptor isoforms, A and B, as well as some other less common splice variants have been identified and they are all encoded by the same 8 exons gene. [20] [21] [22] [23] Like other steroid nuclear receptors, the full-length protein, isoform B, can be divided into 4 functional regions, namely a variable N-terminal region followed by a highly conserved DNA-binding domain, variable hinge region and moderately conserved ligand binding domain. [20] [21] The ligand binding site, known as AF2 domain , is expressed by exons 4-8, corresponding to 253 amino acids, and its structure is of great interest to SPRM development. [24] It consists of 10 α-helices (H1, H3-H12) forming 3 layered bundle entwined with 4 β-sheets . H12 is a condensed contiguous unit composed of helices 10 and 11, which has been suggested to participate in the process of co-activator binding. [25] The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation which favors the binding of coactivator proteins which in turn favors upregulation of gene transcription. [25] The second is an antagonistic conformation which in contrast favors the binding of corepressors and as a consequence down regulation of gene expression. Full agonists such as progesterone, which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. [25] Conversely full antagonists such as aglepristone strongly shift the equilibrium in the antagonist direction. Finally, the overall ratio of concentrations of coactivator to corepressor may differ in different cell types. [25]

G protein-coupled receptor

At the turn of the millennium it was apparent that progesterone activity was not mediated only via transcription factor, but also by a membrane-bound G protein-coupled receptor designated as 7TMPR. When the receptor is activated it blocks adenylyl cyclase, leading to decreased biosynthesis of the intracellular second-messenger cAMP. [24]

Downstream mechanisms

Since the 1990s it has been evident that the two major receptor isomers, A and B, are functionally distinct within the female reproductive system. Researches aimed at expression profile of the isomers suggests that the isomers are expressed in different tissues at different times throughout the menstrual cycle. [12] The PR-B has been found to be upregulated in the stroma and glandular epithelium during follicular phase, but is down-regluated in both tissues during luteal phase. On the contrary, PR-A is upregulated in both tissue types in the follicular phase and persists in the stromal tissue during the late luteal phase. [12] Studies have shown that PR-B activation is important for growth and development of the mammary gland, whereas PR-A has a significant role in normal reproductive function and ovulation. As well, in vitro researches have demonstrated that under identical conditions, the PR-B works as stronger transactivator of reporter genes, while PR-A is able to transrepress PR-B and other steroid receptors. [24] Various reasons have been found for this variety of function between the isoforms. [26] First to mention is that progesterone receptor isoform A lacks 164 N-terminal amino acids compared to isomer B, depriving it of the AF-3 activation function due to loss of B-upstream segment, which leaves it with only 2 activation functions. [27] Also, studies of mechanism have shown difference in cofactor recruitment between the isoforms. Due to these functional differences, one can see why there is an interest of developing a drug that can selectively target the receptor isoforms. Development of SPRMs has, in some cases, been focused on targeting these two different isoforms. [24] [26] [27]

SPRM interaction with receptor binding pockets

Certain interactions between ligand and progesterone receptor have been described to be important for ligand binding (Fig. 2). Crystallography studies of progesterone bound to its receptor have revealed an important hydrogen bond interaction between the progesterone electron-withdrawing 3-keto group and the residues Gln 725 of helix-3 and Arg 766 of helix-5, which are held in position by a structural water molecule. [26] This interaction has been shown to be present in interaction with various other ligands, e.g. mifepristone, tanaproget and asoprisnil and thus can be considered to be vital interaction for function of both agonists and antagonists. [28] Furthermore, progesterone and tanaproget, have been found to make a hydrogen bond with Asn 719 in helix-3, giving an opportunity of higher selectivity and affinity, however, the SPRM asoprisnil has been found not to interact with this residue. [26] Even though the polar residue Thr894 is in close proximity to the C20 carbonyl group of progesterone there is not formed any hydrogen bond between these chemical groups. It is important to note the Thr894 has been found to interact with other ligands. [26] [28]

Stabilization of helixes.jpg
Helix-3 stabilizes helix-12 in the progesterone receptor
Asoprisnil-1.jpg
Increased stabilization of helix-12 caused by agonistic interaction of asoprisnil
Mifepristone.jpg
Destabilization of helix-12 and helix-3 interaction caused by antagonist binding of mifepristone to progesterone receptor
Figure 2: Ligand-progesterone receptor binding interaction

Various studies have described the presence of a hydrophobic pocket, referred as 17α pocket, which consists of Leu 715, Leu718, Phe 794, Leu797, Met 801 and Tyr 890 and appears to provide additional room for ligand expansion irrespective of agonism or antagonism. The 17α pocket, along with Met756 and Met759 within helix-5, as well as Met909, show a surprising flexibility in accommodation of various ligands, making the progesterone receptor very adaptive when it comes to binding. [26] Studies comparing the conformational changes in helix-12 contributing to agonistic and antagonistic effects have shown an important hydrogen interaction with Glu 723 residue of helix-3. At inactive state the Glu723 stabilizes conformation of helix-12 by forming a hydrogen bond to main chain amines in Met908 and Met909. [26] [28] When a ligand conducts an agonist effect, such as the oxime group of asoprisnil interacting with agonist binding pocket, then the hydrogen bond interaction between the previously mentioned residues in helix-12 and helix-3 strengthens, leading to docking and recruitment of coactivators. However, when an antagonist, e.g. mifepristone, interacts with this hydrogen bond system then its dimethylamine group clashes in to Met909 and destabilizes helix-12, causing a conformational change, which promotes the recruitment of corepressors. [26] [28]

Figure 3: Mechanism of action of SPRMs. In this figure, the SPRM is designated a hormone and the progesterone receptor is designated NR (nuclear receptor). Nuclear receptor action.png
Figure 3: Mechanism of action of SPRMs. In this figure, the SPRM is designated a hormone and the progesterone receptor is designated NR (nuclear receptor).

Mechanism of action

When SPRMs bind to the progesterone receptor, the equilibrium between the two conformational states is more closely balanced and hence more easily perturbed by differences in the cellular environment. In tissues where the concentration of coactivators is higher than corepressors, the excess coactivators drive the equilibrium in the agonist direction. Conversely in tissues where corepressor concentration is higher the equilibrium is driven in the antagonist direction. [29] [30] Hence SPRMs display agonist activity in tissues where coactivators predominate and antagonist activity where corepressors are in excess.

When inactive the progesterone receptor, as for other steroid receptor, forms a complex consisting of itself, heat shock proteins (hsp70, hsp90) and immunophilins. [31] [32] Upon activation, due to hormone binding to ligand binding pocket, the receptor complex has been shown to dissociate, triggering nuclear import and giving the receptor the property of dimerisation (Fig. 3). In the nucleus the dimer interacts with progesterone hormone response element in the DNA causing upregulation or downregulation of the gene. [33] [34] [35] [36] Various studies have demonstrated that it affects expression of up to 100 different genes, depending on receptor isomer. [26] In the action of agonism there occur conformational changes, where alpha helices 3, 4 and 12 create a docking surface for coactivator proteins, which act as bridging factors between the receptor and the general transcription machinery. [37] [38] However, the antagonist prevents proper packing of alpha helix 12 against helices 3 and 4, impairing the receptor’s ability to interact with coactivators, which allows recruitment of corepressor, such as SMRT and NCoR. [39] Due to the minimal recruitment of corepressors during agonist binding then there has been postulated by Liu et al., 2002, that the ratio between coactivators vs. corepressors recruitment might be the determinant whether compound is considered to be an agonist, antagonist or mixed agonist-antagonist. [40] The selective progesterone receptor modulators have been described as agents with mixed agonist-antagonist activity and thus the mechanism of action must be due to a balance of these functions.

Structure-activity relationships

Steroidal SPRMs

Figure 4: Structure-activity relationships in mifepristone analogs SAR of Mifepristone analogs.png
Figure 4: Structure–activity relationships in mifepristone analogs

The research on mifepristone analogs, mainly focused on the improvement of the ratio of antiprogestational/antiglucocorticoid activity, [1] [41] led to the discovery of SPRMs. [42] Modifications of or near the 17-alpha propinyl group (Fig. 4) on the D ring play a key role in binding to the progesterone receptor and/or glucocorticoid receptor. [41] [42] [43] Minor changes in the 17-alpha region generate antiprogestins with reduced antiglucocorticoidal activity, where alpha refers to an absolute steroidal stereodescriptor. [41] [42] [43] [44] [45] [46] It seems that hydrophobic 17-alpha substituents such as 17-alpha ethyl and 17-alpha (1´-pentynyl) give rise to antiprogestational activity superior to that of mifepristone. [43] Substitution on the 17-alpha position involving phenyl group with small, electron-withdrawing substituents, such as F and CF3, on the para-position was also found to greatly increase the selectivity over glucocorticoid receptor as well as the potency of resulting compounds. Same substitution at the ortho- or meta- position led to decrease in selectivity. Bulky substituents, such as tert-butyl, in this region decrease the progesterone potency. [45]

The available biological and X-ray data suggest that the substitution of 4-(dimethylamino) phenyl group at the C11 (Fig. 4) position determines the degree of agonistic and antagonistic activity. [41] [42] Small substituents like methyl or vinyl give rise to potent progesterone receptor-agonistic properties [42] whereas substituted phenyl derivatives show different degrees of antagonistic activity. [42] [43] [44] There is an indication, when substituted by various nitrogen heterocycles, that the most agonistic are compounds with a clear maximum in the negative electric potential in the region of the meta- and para- atoms of the aryl ring [47] whereas compounds that lack a center of electronegativity in this region have the highest antagonistic activity. [26] [47]

Modification of the core steroidal structure affects the mode of binding to the progesterone receptor. [45] [48] The substitution of C7 (Fig. 4) by oxygen atom has been investigated and these mifepristone-like oxasteroids showed increased selectivity over glucocorticoid receptor but were less potent than mifepristone. [45] [49]

Nonsteroidal SPRMs

Progesterone receptor modulators with unique nonsteroidal structures are currently in the early stages of development (Fig. 5-12). Variety of new types of progesterone receptor antagonists with different degree of potency has been reported and show a remarkable structural diversity which can be seen in table below. Various lead compounds have also been identified as new progesterone receptor agonists. They can also be viewed in the table. [26]

Antagonists
Figure 5: Progesterone receptor antagonists based on a pyrazole core Progesterone receptor antagonists based on a pyrazole core with small lipophilic substituents.png
Figure 5: Progesterone receptor antagonists based on a pyrazole core
Figure 6: Trisubstituted thiophenes as PR antagonists with low potency Trisubstituted thiophenes as PR antagonists with low potency.png
Figure 6: Trisubstituted thiophenes as PR antagonists with low potency
Figure 7: Indole derivatives as PR antagonists with preference of electron withdrawing groups on the aromatic ring Indole derivatives as PR antagonists with preference of electron withdrawing groups on the aromatic ring.png
Figure 7: Indole derivatives as PR antagonists with preference of electron withdrawing groups on the aromatic ring
Figure 8: 6-aryl-1,3dihydrobenzimidazol -2ones substituent at the 1-position of the benzimidazolone 6-aryl-1,3 dihydrobenzimidazol-2ones with lipophilic substituent at the 1-position of the.png
Figure 8: 6-aryl-1,3dihydrobenzimidazol -2ones substituent at the 1-position of the benzimidazolone
Figure 9: PR antagonists with an aryl group inked to benzoxazin-2-one core through an amino group at the 6-position PR antagonists with an aryl group inked to benzoxazin-2-one core through an amino group at.png
Figure 9: PR antagonists with an aryl group inked to benzoxazin-2-one core through an amino group at the 6-position
Agonists
Figure 10: 6-(5-cyanopyrrol-2-yl) benzoxazine- 2-thiones 6-(5-cyanopyrrol-2-yl) benzoxazine- 2-thiones, a class of potent and selective PR agonists.png
Figure 10: 6-(5-cyanopyrrol-2-yl) benzoxazine- 2-thiones
Figure 11: Tetrahydrobenzindolone lead compound with high selectivity Tetrahydrobenzindolone lead compound with high selectivity.png
Figure 11: Tetrahydrobenzindolone lead compound with high selectivity
Figure 12: Arylpyrazolines and aryldiazepines as PR modulators Arylpyrazolines and aryldiazepines as PR modulators.png
Figure 12: Arylpyrazolines and aryldiazepines as PR modulators

Drugs

Members include:

SPRM have been suggested for multiple gynaecological applications, such as contraception and emergency contraception, treatment for endometriosis, uterine leiomyoma and as a hormone replacing therapy in post-menopausal women. [50] SPRM activity is mainly mediated via the progesterone receptor, where the endometrium is the major target tissue. In contrast to conventional progesterone antagonists, the SPRMs eliminate the ability to terminate pregnancy due to their mixed antagonist/agonist profile. Since SPRMs have a low affinity for the estrogen receptor, they are not thought to induce post-menopausal associated bone loss. [12] SPRMs use has been associated with endometrial metaplasia , which calls for the need for a long-term safety assessment. [12]

CompoundChemical structure
Ulipristal acetate
Figure 13: Ulipristal acetate skeletal Ulipristal acetate skeletal.svg
Figure 13: Ulipristal acetate skeletal
Figure 13
Asoprisnil
Asoprisnil Asoprisnil.svg
Asoprisnil
Figure 14
Telapristone
Telapristone Telapristone.svg
Telapristone
Figure 15

Ulipristal acetate

Ulipristal acetate (also known as CDB-2914) [51] (Fig. 13) is an 11-β aryl substituted SPRM that has been available as an emergency contraception in Europe since 2009 and was FDA approved in 2010. [52] It’s also marketed as a treatment for uterine leiomyoma in North America and Europe. As an emergency contraception ulipristal acetate has shown to be potent up to 120h after unprotected intercourse, compared to 72h potency of current emergency contraceptions. [50] In post-menopausal endometrium the compound seems to have antagonistic effect or progesterone receptor, indicating potential use in menopausal treatment but this has yet to be confirmed. [12]

Asoprisnil

Asoprisnil (J867) is a steroidal 11β-benzaldoxime substituted SPRM (Fig. 14). [15] The geometry of its oxime group is suggested to play a major role in the in vitro potency. [26] It has been suggested as a treatment for leiomyoma and endometriosis [53] and it is the first SPRM in the clinical development of endometriosis treatment to reach an advanced phase. [54]

Telapristone

Telapristone (CDB-4124), also known as Proellex (Fig. 15), entered phase II clinical trial for in treatment uterine fibroids in 2014 [55] and has a planned phase II clinical trial for alleviation of symptoms of endometriosis in early 2016. [56] [57] It has also been suggested to have chemopreventive effects. [58]

Uses

SPRMs are under development for the following uses:

While these SPRMs have been effective for the treatment of uterine fibroids, development of side effects such as endometrial thickening has limited their administration to no longer than three to four months. [60]

Future

Due to its antiglucocorticoidal activity, mifepristone is investigated for its therapeutical potential in indications like Cushing's syndrome, Alzheimer's disease or psychosis. Beside that SPRMs are under development for various gynecological applications, including estrogen-free contraception, uterine leiomyoma and endometriosis. [62]

See also

Related Research Articles

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">Uterine fibroid</span> Medical condition with benign tumors of uterus

Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder, causing a frequent need to urinate. They may also cause pain during penetrative sex or lower back pain. A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.

<span class="mw-page-title-main">Progesterone receptor</span> Cytoplasmic receptor protein found inside cells

The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.

<span class="mw-page-title-main">Mineralocorticoid receptor</span> Nuclear receptor that mediates the effects of the mineralocorticoid hormone Aldosterone

The mineralocorticoid receptor, also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Asoprisnil</span> Chemical compound

Asoprisnil is a synthetic, steroidal selective progesterone receptor modulator that was under development by Schering and TAP Pharmaceutical Products for the treatment of uterine fibroids. In 2005, phase III clinical trials were discontinued due to endometrial changes in patients.

<span class="mw-page-title-main">Telapristone</span> Chemical compound

Telapristone, as telapristone acetate, is a synthetic, steroidal selective progesterone receptor modulator (SPRM) related to mifepristone which is under development by Repros Therapeutics for the treatment of breast cancer, endometriosis, and uterine fibroids. It was originally developed by the National Institutes of Health (NIH), and, as of 2017, is in phase II clinical trials for the aforementioned indications. In addition to its activity as an SPRM, the drug also has some antiglucocorticoid activity.

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and G protein-coupled receptors.

<span class="mw-page-title-main">Antiprogestogen</span> Class of compounds

Antiprogestogens, or antiprogestins, also known as progesterone antagonists or progesterone blockers, are a class of drugs which prevent progestogens like progesterone from mediating their biological effects in the body. These drugs competitively inhibit progestin at progesterone receptors. They act by blocking the progesterone receptor (PR)and/or inhibiting or suppressing progestogen production. Antiprogestogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiandrogens.

<span class="mw-page-title-main">BMS-564,929</span> Chemical compound

BMS-564,929 is an investigational selective androgen receptor modulator (SARM) which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men ("andropause"). These symptoms may include depression, loss of muscle mass and strength, reduction in libido and osteoporosis. Treatment with exogenous testosterone is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the prostate gland, which can lead to benign prostatic hypertrophy and even prostate cancer. This means there is a clinical need for selective androgen receptor modulators, which produce anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.

<span class="mw-page-title-main">Enobosarm</span> Investigational selective androgen receptor modulator

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.

<span class="mw-page-title-main">Onapristone</span> Chemical compound

Onapristone is a synthetic and steroidal antiprogestogen with additional antiglucocorticoid activity which was developed by Schering and described in 1984 but was never marketed. It is a silent antagonist of the progesterone receptor (PR), in contrast to the related antiprogestogen mifepristone. Moreover, compared to mifepristone, onapristone has reduced antiglucocorticoid activity, shows little antiandrogenic activity, and has 10- to 30-fold greater potency as an antiprogestogen. The medication was under development for clinical use, for instance in the treatment of breast cancer and as an endometrial contraceptive, but was discontinued during phase III clinical trials in 1995 due to findings that liver function abnormalities developed in a majority patients.

<span class="mw-page-title-main">Vilaprisan</span> Chemical compound

Vilaprisan is a synthetic and steroidal selective progesterone receptor modulator (SPRM) which is under development by Bayer HealthCare Pharmaceuticals for the treatment of endometriosis and uterine fibroids. It is a potent and highly selective partial agonist of the progesterone receptor (PR). As of 2017, the drug is in phase II clinical trials for the aforementioned indications.

<span class="mw-page-title-main">Asoprisnil ecamate</span> Chemical compound

Asoprisnil ecamate (INN) is a synthetic, steroidal selective progesterone receptor modulator (SPRM) which was under development for the treatment of endometriosis, uterine fibroids, and menopausal symptoms but was discontinued. It is a potent and highly selective ligand of the progesterone receptor with mixed agonistic and antagonistic activity and much reduced antiglucocorticoid activity relative to mifepristone. The drug reached phase III clinical trials for the aforementioned indications prior to its discontinuation.

<span class="mw-page-title-main">5α-Dihydronorethisterone</span> Chemical compound

5α-Dihydronorethisterone is a major active metabolite of norethisterone (norethindrone). Norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.

References

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