A selective progesterone receptor modulator (SPRM) is an

agent Agent may refer to: Espionage, investigation, and law *, spies or intelligence officers * Law of agency, laws involving a person authorized to act on behalf of another ** Agent of record, a person with a contractual agreement with an insuran ...

that acts on the

progesterone receptor 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. In humans, PR is encoded by a single ''PGR'' gene resi ...

(PR), the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...

s like

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

. A characteristic that distinguishes such substances from full receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s (e.g., progesterone,

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...

s) and full

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.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.

History

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

antagonist was introduced by the name RU 38486 (RU 486,

mifepristone Mifepristone, and also known by its developmental code name RU-486, is a drug typically used in combination with misoprostol to bring about a medical abortion during pregnancy. This combination is 97% effective during the first 63 days (9 wee ...

). However, the clinical limitation of mifepristone due to its relatively high binding affinity for

glucocorticoid receptor The glucocorticoid receptor (GR or GCR) also known by its gene name ''NR3C1'' ( nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol. The GR is expressed in almost every cell in the bod ...

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 Asoprisnil ( INN; developmental code name J-867) 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 ...

, which failed phase 3 clinical trial in 2008, and

ulipristal acetate Ulipristal acetate, sold under the brand name Ella among others, is a medication used for emergency contraception (birth control) and uterine fibroids. As emergency contraception it should be used within 120 hours of vaginally penetrating inte ...

, the first SPRM on the market (2009 in Europe).

Progesterone receptor

Receptor

As a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

, the

(Fig. 1) is a member of the ligand-dependent

nuclear hormone receptor 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 exp ...

family. Two major progesterone receptor

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

, A and B, as well as some other less common splice variants have been identified and they are all encoded by the same 8

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s gene. Like other steroid

nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These intracellular receptor (biochemistry) ...

, the full-length protein, isoform B, can be divided into 4 functional regions, namely a variable

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

region followed by a highly conserved

DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...

, variable hinge region and moderately conserved ligand binding domain. The ligand binding site, known as AF2 domain, is expressed by exons 4-8, corresponding to 253

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

, and its structure is of great interest to SPRM development. 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. The second is an antagonistic conformation which in contrast favors the binding of

corepressor In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membra ...

s 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. 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.

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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

designated as 7TMPR. When the receptor is activated it blocks

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, leading to decreased biosynthesis of the intracellular second-messenger cAMP.

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 The human female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. The reproductive system is immature at birth and develops at puberty to be able to release matured ov ...

. Researches aimed at expression profile of the isomers suggests that the isomers are expressed in different tissues at different times throughout the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

. The PR-B has been found to be upregulated in the stroma and glandular epithelium during

follicular phase The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a full ...

, but is down-regluated in both tissues during

luteal phase The menstrual cycle is on average 28 days in length. It begins with Menstruation, menses (day 1–7) during the follicular phase (day 1–14), followed by ovulation (day 14) and ending with the luteal phase (day 14–28). While historically, medi ...

. 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. Studies have shown that PR-B activation is important for growth and development of the

mammary gland A mammary gland is an exocrine gland that produces milk in humans and other mammals. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primates (for example, human ...

, whereas PR-A has a significant role in normal reproductive function and

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

. As well, ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' researches have demonstrated that under identical conditions, the PR-B works as stronger transactivator of

reporter gene Reporter genes are molecular tools widely used in molecular biology, genetics, and biotechnology to study gene function, expression patterns, and regulatory mechanisms. These genes encode proteins that produce easily detectable signals, such as ...

s, while PR-A is able to transrepress PR-B and other steroid receptors. Various reasons have been found for this variety of function between the isoforms. 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. 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.

SPRM interaction with receptor binding pockets

Certain interactions between

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

and progesterone receptor have been described to be important for ligand binding (Fig. 2).

Crystallography Crystallography is the branch of science devoted to the study of molecular and crystalline structure and properties. The word ''crystallography'' is derived from the Ancient Greek word (; "clear ice, rock-crystal"), and (; "to write"). In J ...

studies of progesterone bound to its receptor have revealed an important

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

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. 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. Furthermore, progesterone and tanaproget, have been found to make a hydrogen bond with Asn₇₁₉ in helix-3, giving an opportunity of higher selectivity and affinity, however, the SPRM asoprisnil has been found not to interact with this residue. 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. Various studies have described the presence of a

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

pocket, referred as 17α pocket, which consists of Leu₇₁₅, Leu₇₁₈, Phe₇₉₄, Leu₇₉₇, Met₈₀₁ and Tyr₈₉₀ 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. Studies comparing the conformational changes in helix-12 contributing to agonistic and antagonistic effects have shown an important hydrogen interaction with Glu₇₂₃ residue of helix-3. At inactive state the Glu₇₂₃ stabilizes conformation of helix-12 by forming a hydrogen bond to main chain

amines In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

in Met₉₀₈ and Met₉₀₉. When a ligand conducts an agonist effect, such as the

oxime In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...

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 Dimethylamine is an organic compound with the formula (CH3)2NH. This secondary amine is a colorless, flammable gas with an ammonia-like odor. Dimethylamine is commonly encountered commercially as a solution in water at concentrations up to around ...

group clashes in to Met₉₀₉ and destabilizes helix-12, causing a conformational change, which promotes the recruitment of corepressors.

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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

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. 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. However, the antagonist prevents proper packing of

alpha helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

12 against helices 3 and 4, impairing the receptor’s ability to interact with coactivators, which allows recruitment of

, 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

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. 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. 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. Small substituents like methyl or vinyl give rise to potent progesterone receptor-agonistic properties whereas substituted phenyl derivatives show different degrees of antagonistic activity. 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 whereas compounds that lack a center of

electronegativity Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the ...

in this region have the highest antagonistic activity. 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 compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but ...

s have also been identified as new progesterone receptor agonists. They can also be viewed in the table.

Drugs

Members include: *

Ulipristal acetate Ulipristal acetate, sold under the brand name Ella among others, is a medication used for emergency contraception (birth control) and uterine fibroids. As emergency contraception it should be used within 120 hours of vaginally penetrating inte ...

("Ella") *

Asoprisnil Asoprisnil ( INN; developmental code name J-867) 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 ...

(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 Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

uterine leiomyoma Uterine fibroids, also known as uterine leiomyomas, fibromyoma or fibroids, are benign smooth muscle tumors of the uterus, part of the female reproductive system. Most people with fibroids have no symptoms while others may have painful or h ...

and as a hormone replacing therapy in post-menopausal women. SPRM activity is mainly mediated via the progesterone receptor, where the

endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

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. SPRMs use has been associated with endometrial

metaplasia Metaplasia () is the transformation of a cell type to another cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abnormal stimulus. In simplistic terms, it is as if the ...

, which calls for the need for a long-term safety assessment.

Ulipristal acetate

Ulipristal acetate (also known as CDB-2914) (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. 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.

Asoprisnil

(J867) is a steroidal 11β-benzaldoxime substituted SPRM (Fig. 14). The geometry of its oxime group is suggested to play a major role in the ''in vitro'' potency. It has been suggested as a treatment for leiomyoma and endometriosis 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 Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

. Beside that SPRMs are under development for various gynecological applications, including estrogen-free contraception, uterine leiomyoma and endometriosis.

References

{{Progesterone receptor modulators Selective progesterone receptor modulators