A selective progesterone receptor modulator ( SPRM ) is an agent acting on a progesterone receptor. Characteristics that distinguish substances such as full receptor agonists (such as progesterone) and full antagonists (such as aglepristone) are that their actions differ in different tissues, ie agonists in some tissues while antagonists in others. This mixed action profile leads to stimulation or inhibition in a tissue-specific way, which further increases the likelihood of separating undesirable adverse effects from the development of candidate prescription progesterone synthetic drugs.
Video Selective progesterone receptor modulator
History
Since the discovery of the hormone progesterone in the mid-1930s. and especially after the discovery of its receptor in 1970, there is significant interest in developing antagonistic agents for therapeutic use. Various analogue progesterone, known as progestin, was synthesized and in 1981 the first progesterone receptor antagonist was introduced under the name RU 38486 (RU 486, mifepristone). However, the clinical limitations of mifepristone due to its relatively high relative affinity for glucocorticoid receptors compared with progesterone receptors have triggered the demand for more selective progesterone antagonists to minimize the risk of adverse events. As a contribution, the so-called Selective Progesterone Receptor Modulator (SPRMs) has been developed. They have been described as agents with antagonistic and agonistic effects on progesterone receptors in tissue-specific ways, while minimizing interactions with other steroid receptors. Against progesterone antagonists, SPRM agonist mixtures of antagonists, due to their intrinsic progesterone agonist activity, are absent or only minimal effects on termination of pregnancy and are thus ideal for treating gynecological conditions without losing the potential for pregnancy. Both steroid and non steroid SPRMs have been described and the most prominent examples are asoprisnil, which failed phase 3 clinical trials in 2008, and ulipristal acetate, the first SPRM on the market (2009 in Europe).
Maps Selective progesterone receptor modulator
Progesteron receptor
Receptor
As a protein, the progesterone receptor (Fig. 1) is a member of the ligand-dependent nuclear hormone receptor family. 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 8th exon gene. Like other steroid nuclear receptors, the full-length protein, B isoform, can be divided into 4 functional regions, ie the N-terminal region of the variable followed by a highly sustainable DNA binding domain, the variable hinge region and the ligand bound ligand domain. The ligand binding site, known as the AF2 domain, is expressed by exon 4-8, corresponding to 253 amino acids, and the structure is very attractive for SPRM development. It consists of 10? -helices (H1, H3-H12) form 3 layered bundles intertwined with 4? -window. H12 is a co-condensed unit consisting of helix 10 and 11, which has been suggested to participate in the co-activator binding process. The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation that supports the binding of a protein coactivator which in turn supports the regulation of gene transcription. The second is antagonistic conformation which in turn supports the binding of corepressors and as a consequence decreases the regulation of gene expression. A full agonist such as progesterone, which features agonist properties in all tissues, greatly shifts the conformational balance in the direction of agonist. In contrast a full antagonist such as aglepristone greatly shifts the equilibrium in the direction of the antagonist. Finally, the ratio of coactivator concentrations to the overall corepressor may differ in different cell types.
G protein-coupled receptor
At the turn of the millennium it is clear that the activity of progesterone is not mediated solely by transcription factors, but also by membrane bound membrane protein recipients defined as 7TMPR. When the receptor is activated, it blocks adenylyl cyclase, which causes a decrease in biosynthesis of intracellular second-messenger cAMP.
Downstream mechanism
Since the 1990s it has been shown that the two major receptor isomers, A and B, are functionally different in the female reproductive system. Research aimed at isomer expression profiles shows that the isomers are expressed in different tissues at different times throughout the menstrual cycle. PR-B has been found to be regulated in the stroma and glandular epithelium during the follicular phase, but decreases in both tissues during the luteal phase. In contrast, PR-A is regulated in both tissues in the follicular phase and settled in the stromal tissue during the final luteal phase. Studies have shown that activation of PR-B is important for the growth and development of the mammary glands, whereas PR-A has a significant role in normal reproductive function and ovulation. In addition, in vitro studies have shown that under the same conditions, PR-B works as a more powerful reporter gene transactivator, while PR-A is able to transcend PR-B and other steroid receptors. Various reasons have been found for various functions between isoforms. The first to mention is that the progesterone isoform A receptor lacks 164 N-terminal amino acids compared to the B isomer, depriving it of the AF-3 activation function due to the loss of the B-upstream segment, leaving it with only 2 activation functions. Also, the mechanism studies show differences in cofactor recruitment between isoforms. Due to these functional differences, one can see why there is an interest in developing drugs that can selectively target receptor isoforms. The development of SPRMs, in some cases, is focused on targeting these two different isoforms.
SPRM interaction with pouch binding receptor
Certain interactions between ligand and progesterone receptors have been described as being important for binding ligands (Figure 2). The study of crystallographic progesterone bound to its receptor has revealed an important hydrogen bonding interaction between the 3-keto group of electron progesterone and the residual Gln 725 of helix-3 and Arg 766 helix-5 , which are held in position by structural water molecules. This interaction has been shown to be present in interactions with other ligands, eg. mifepristone, tanaproget and asoprisnil and thus can be regarded as a vital interaction for the functions of agonists and antagonists. Furthermore, progesterone and tanaproget, have been found to make hydrogen bonds with Asn 719 in helix-3, providing higher selectivity and affinity opportunities, however, asoprisnil SPRM has been found to not interact with this residue. Interestingly, although the polar residue Thr 894 is near the progesterone carbonate group C 20 no hydrogen bonds are formed between these chemical groups. It is important to note that Thr 894 has been found to interact with other ligands.
Various studies have described the existence of hydrophobic pockets, called 17? pocket 794 , Leu 797 , Meet 801 and Tyr 890 and appears to provide additional space for expansion ligands regardless of agonism or antagonism. 17? pocket, together with Met 756 and Met 759 in helix-5, as well as Met 909 , showing surprising flexibility in accommodation of various ligands, making receptors progesterone is highly adaptive when it comes to binding. Studies comparing conformational changes in helix-12 contributing to agonistic effects and antagonists have shown important hydrogen interactions with Glu 723 residuals of helix-3. In an inactive state, Glu 723 stabilizes the helix-12 conformation by forming a hydrogen bond to the amine main chain at Met 908 and Met 909 . When the ligand performs an agonist effect, such as the oxime group of asoprisnil interacting with the agonist binding pouch, the hydrogen bond interaction between the previously mentioned residues in helix-12 and helix-3 strengthens, leading to docking and recruitment coactivators. However, when the antagonists, eg. mifepristone, interacting with this hydrogen bonding system then dispersing its dimethylamine group to Met 909 and destabilizing the helix-12, causing a conformational change, prompting the recruitment of the korepresor.
Action mechanism
When the SPRM binds to the progesterone receptor, the balance between the two conformational states is more closely balanced and therefore more easily distracted by differences in the cellular environment. In tissues where concentrations of coactivators are higher than corepressors, excessive coactivators push the balance toward the agonist. Conversely in tissues where the higher corepressor concentration of the balance is pushed toward the antagonist. Therefore SPRMs display agonist activity in networks where coactivators dominate and antagonist activity in which corepressors overeat.
When progesterone is not active progesterone receptors, such as other steroid receptors, form a complex consisting of itself, heat shock proteins (hsp70, hsp90) and immunophilins. After activation, due to hormone bonding in the ligand binding sac, the receptor complex has been shown to dissociate, triggering nuclear imports and giving the dimerization properties (Fig 3). In the nucleus, the dimer interacts with the progesterone hormone response element in DNA that causes regulation or downregulation of genes. Various studies have shown that it affects the expression of up to 100 different genes, depending on the receptor isomer. In the action of agonism there is a conformational change, in which alpha helices 3, 4 and 12 create a docking surface for the coactivation protein, which acts as a connecting factor between the receptor and the general transcription machine. However, antagonists prevent proper packaging of alpha helix 12 against helices 3 and 4, interfering with the receptor's ability to interact with the coactivator, which allows recruitment of corepressors, such as SMRT and NCoR. Because of the minimal recruitment of corepressors during agonist binding it has been postulated by Liu et al., 2002, that the ratio between coactivators vs. recruitment corepressors may be a determinant of whether the compound is considered an agonist, antagonist agonist or antagonists. Selective progesterone receptor modulators have been described as agents with mixed agonist-antagonist activity and thus the working mechanism must be due to the balance of these functions.
Activity-structure relations
Steroidal SPRMs
Research on mifepristone analogues, primarily focused on increasing the antiprogestational/antigenocorticoid activity ratios, led to the discovery of SPRMs. Modification or proximity to the 17-alpha propyl group (Figure 4) in the D ring plays a key role in binding to the progesterone receptor and/or glucocorticoid receptor. Small changes in the 17-alpha region produce antiprogestin with reduced antigluccorticoid activity, where alpha refers to an absolute steroid steroid. It appears that 17-alpha hydrophobic substituents such as 17-alpha ethyl and 17-alpha (1'-pentynyl) produce superior antiprogestational activity than mifepristone. Substitutions at 17-alpha positions involving phenyl groups with small substituents attracting electrons, such as F and CF 3 , in para -positions are also found to be greatly increased. selectivity of the glucocorticoid receptor as well as the potential of the resulting compound. The same substitution in ortho - or meta - causes a decrease in selectivity. Large substituents, such as tert -butyl, in this region lower the potential for progesterone.
Available biological and X-ray data show that the substitution of the phenyl 4 (dimethylamino) group at position C11 (Figure 4) determines the level of agonist and antagonist activity. Small substituents such as methyl or vinyl lead to strong progesterone-receptor-agonist properties while substituted phenyl derivatives show different levels of antagonistic activity. There are indications, when replaced by various heterocycles of nitrogen, the most agonistic is the clearest clear maximum compound in the negative electrical potential in the region of meta and the - atoms of the aryl ring while the compound having no central electronegativity in this region has the highest antagonistic activity.
Modification of the nuclear steroid structure affects the binding mode of the progesterone receptor. Substitution of C7 (Figure 4) by oxygen atoms has been investigated and this mifepristone-like oxasteroid exhibits increased selectivity to glucocorticoid receptors but is less potent than mifepristone.
Nonsteroid SPRM
The progesterone receptor modulator with a unique nonsteroidal structure is currently in the early stages of development (Fig. 5-12). Various new types of progesterone receptor antagonists with varying degrees of potency have been reported and demonstrated remarkable structural diversity that can be seen in the table below. Various lead compounds have also been identified as new progesterone receptor agonists. They can also be seen at the table.
Drugs
Members include:
- Ulipristal acetate ("Ella")
- Asoprisnil (J867; uncertain status)
- Telapristone (CDB-4124; Proellex, Progenta; in development)
SPRM has been recommended for several gynecological applications, such as contraception and emergency contraception, treatment for endometriosis, uterine leiomioma and as hormone replacement therapy in postmenopausal women. SPRM activity is primarily mediated through progesterone receptors, in which the endometrium is the primary target tissue. Unlike conventional progesterone antagonists, SPRMs eliminate the ability to terminate pregnancy due to their mixed antagonistic/agonist profile. Because the SPRM has a low affinity for estrogen receptors, they do not think to induce bone-related postmenopausal loss. The use of SPRMs has been linked to endometrial metaplasia, which calls for the need for long-term safety assessment.
Ulipristal acetate
Ulipristal acetate (also known as CDB-2914) (Figure 13) is 11-? Aril replaced SPRM which has been available as an emergency contraceptive in Europe since 2009 and approved by the FDA in 2010. It is also marketed as a treatment for uterine leiomioma in North America and Europe. As an emergency contraceptive, ulipristal acetate proved effective up to 120 hours after unprotected intercourse, compared to 72 hours of current emergency contraceptive potential. In post-menopausal endometrium, the compound appears to have antagonistic or progesterone receptor effects, suggesting potential use in the treatment of menopause but this has not yet been confirmed.
Asoprisnil
Asoprisnil (J867) is a steroidal 11? -benzaldoxime substituted SPRM (Fig 14). The geometry of the oxyme group is suggested to play a major role in the potential in vitro . It has been suggested as a treatment for leiomyomas and endometriosis and it is the first SPRM in the clinical development of endometriosis treatment to achieve an advanced phase.
Telapristone
Telapristone (CDB-4124), also known as Proellex (Figure 15), enters phase II clinical trials for the treatment of uterine fibroids by 2014 and has phase II clinical trials planned to relieve the symptoms of endometriosis in early 2016. It has also been it is advisable to have a chemopreventive effect.
Usage
SPRM is under development for the following uses:
- Asoprisnil and telapristone are both under investigation (2005) for medical treatment of uterine leiomyomas.
- Proellex has completed a number of clinical trials to treat endometriosis and uterine fibroids.
While this SPRM has been effective for the treatment of uterine fibroids, the development of side effects such as endometrial thickening has limited their administration to no more than three to four months.
Future
Because of its anticocorticoid activity, mifepristone is investigated for its therapeutic potential in indications such as Cushing's syndrome, Alzheimer's disease or psychosis. In addition SPRMs are under development for various gynecological applications, including estrogen-free contraceptives, uterine leiomyomas and endometriosis.
See also
- Phytoprogestogen
- Selective androgen receptor modulators
- Selector of selective estrogen receptors
- Selective glucocorticoid receptor agonists
- Selective receptor modulators
References
Source of the article : Wikipedia
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