Selective progesterone receptor modulator

Ever since the discovery of the progesterone hormone in the mid-1930s. and especially after the discovery of its receptor in 1970 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). 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. 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. 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. Both steroidal and non steroidal SPRMs have been described and the most notable examples are asoprisnil, which failed phase 3 clinical trial in 2008, and ulipristal acetate, the first SPRM on the market (2009 in Europe). ==Progesterone 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 8 exons gene. 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. 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. 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. 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 Gln725 of helix-3 and Arg766 of helix-5, which are held in position by a structural water molecule. ==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. 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. 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. Various studies have demonstrated that it affects expression of up to 100 different genes, depending on receptor isomer. 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. 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. 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 s in mifepristone analogs|upright=1.6 The research on mifepristone analogs, mainly focused on the improvement of the ratio of antiprogestational/antiglucocorticoid activity, led to the discovery of SPRMs. 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. Minor changes in the 17-alpha region generate antiprogestins with reduced antiglucocorticoidal activity, where alpha refers to an absolute steroidal stereodescriptor. 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. Modification of the core steroidal structure affects the mode of binding to the progesterone receptor. 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. 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. ==Drugs==

Members include: • Ulipristal acetate ("Ella") • Asoprisnil (J867; status uncertain) • Telapristone (CDB-4124; Proellex, Progenta; under development) 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. 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. (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. 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. and it is the first SPRM in the clinical development of endometriosis treatment to reach an advanced phase. Telapristone Telapristone (CDB-4124), also known as Proellex (Fig. 15), entered phase II clinical trial for in treatment uterine fibroids in 2014 and has a planned phase II clinical trial for alleviation of symptoms of endometriosis in early 2016. It has also been suggested to have chemopreventive effects. ==Uses==

SPRMs are under development for the following uses: • Asoprisnil and telapristone are both under investigation (2005) for the medical treatment of uterine leiomyoma. • Proellex has completed a number of clinical trials to treat endometriosis and uterine fibroids. 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. ==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. ==See also==