Selective estrogen receptor modulator

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Selective estrogen receptor modulator ( SERMs ) is a class of drugs acting on estrogen receptors (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists (ie, full agonists and silent antagonists) is that their actions differ in different tissues, thus providing the possibility to selectively inhibit or stimulate action such as estrogen in various tissues.

SERM is a competitive partial agonist of ER. Different tissues have different levels of sensitivity to and endogenous estrogen activity, so SERMs produce estrogenic or antiestrogenic effects depending on the specific tissue concerned as well as the intrinsic activity percentage (IA) of the SERM. Examples of SERMs with high IA and thus most estrogenic effects are chlorotrianisene, whereas SERM examples with low IA and thus most antiestrogenic effects are ethamoxytriphetol. SERMs such as clomifene and tamoxifen are more in the middle of IA and balance their estrogenic and antiestrogenic action as a comparison. Raloxifene is a more antiestrogenic SERM than tamoxifen; both estrogenic in bone, but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this location.

Video Selective estrogen receptor modulator

Medical use

SERM is used for various estrogen-related diseases. Includes treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction of risk of breast cancer and dyspareunia treatment due to menopause. SERM is also used in combination with conjugated estrogens indicated for the treatment of symptoms of estrogen deficiency, and vasomotor symptoms associated with menopause. SERMs are used depending on the pattern of their actions in various networks:

Tamoxifen is the first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for reducing the risk of breast cancer in women at high risk, and as adjuvant treatment of node carcinoma of positive nodes and nodes, in the ductal in situ . Tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. Side effects including hot flushes and more serious ones are two to three times higher than the relative risk of developing endometrial cancer compared to women of a population that is suitable for age.

Toremifene, a chlorinated tamoxifen derivative, causes less DNA to stir in the liver than is seen with tamoxifen in preclinical studies and is developed to avoid liver carcinoma. It is used as an endocrine therapy in women with stage 4 ER/PR-positive or recurrent metastatic breast cancer and has shown similar efficacy compared with tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.

Raloxifene is used for the prevention and treatment of postmenopausal osteoporosis and prevention of breast cancer in postmenopausal women at high risk with osteoporosis. Preclinical and clinical reports show that it is far less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not shown any effects such as tamoxifen in the uterus but has been associated with side effects such as venous thromboembolism and vasomotor symptoms, including hot flushes.

Ospemifene is an analogue metabolite of toremifene. Unlike tamoxifen, toremifene is not a rat hepatocarcinogen and therefore ospemifene will also be a safer SERM than tamoxifen. It is used for the treatment of moderate to severe dyspareunia, symptoms of vulvar and vaginal atrophy associated with menopause. Clinical data on breast cancer is not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue.

Bazedoxifene is used as a treatment for osteoporosis in postmenopausal women with an increased risk of fracture. It has been proven to be relatively safe and well tolerated. This shows no stimulation of the breast or endometrium and in the first two years, a small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene against raloxifene is that it increases the activity of endothelial nitric oxide synthase and does not conflict with the effect of 17? -estradiol on vasomotor symptoms.

The first selective tissue estrogen complex (TSEC) combines conjugated estrogens and bazedoxifene SERM to blend their activities. Combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of symptoms of estrogen deficiency in postmenopausal non-hysterectomic women. This combination allows for estrogen benefits in relation to relieving vasomotor symptoms without estrogenic stimulation of the endometrium.

Available form

Maps Selective estrogen receptor modulator

Pharmacology

Pharmacodynamics

Binding site

SERM acts on estrogen receptor (ER), which is an intracellular, ligand-dependent transcriptional activator and includes nuclear receptor family. Two different ER subtypes have been identified, ER? and ER? ER? is considered the primary medium in which estrogen signals are transduced at the transcription level and are the dominant ER in the female reproductive tract and mammary glands while ER? especially in vascular endothelial cells, bone, and male prostate tissue. ER? and ER? Concentrations are known to differ in tissues during development, aging or disease. Many of the characteristics are similar between these two types such as size (~ 600 and 530 amino acids) and structures. ER? and ER? share about 97% of the amino acid sequence identity in the DNA binding domain and about 56% in the ligand binder domain (see figure 3). The main difference of the ligand binding domain is determined by Leu-384 and Met-421 in ER ?, which were replaced by Met-336 and Ile-373, respectively, in ER ?. Greater variation on N-terminus between ER? and ER?

The DNA-binding domain consists of two subdomains. One with a proximal box involved in DNA recognition while the other contains a distal box that is responsible for dimerising DNA-dependent domains, DNA-binding. An identical proximal box sequence between ERs? and ER ?, which exhibit similarity and affinity are similar between the two subgroups. The globular protein binding domain DNA contains eight cysteines and allows for the tetrahedral coordination of the two zinc ions. This coordination makes the ER binding to the estrogen response element possible. The binding domain of ligands is a three-tiered structure made of 11 helices and contains pockets for natural or synthetic ligands. Factors that affect the affinity of binding are mainly the presence of phenol groups, molecular size and shape, double bonds and hydrophobicity.

The differential position of the activation function 2 (AF-2) helix 12 in the ligand binder domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In bound-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for NR box motifs contained in coactivators in the canonical order LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unlinked receptors or apo bonds in antagonistic ligand convert the helix 12 away from the LXXLL binding surface which leads to the special binding of leaf-rich motifs, LXXXIXXX (I/L), present to NCoR1 or SMRT corepressors. In addition, some cofactors bind to the ER through the terminal, DNA binding sites or other binding sites. Thus, one compound can be an ER agonist in a network of coactivator-rich but ER antagonists in a rich network of corepressors.

Action mechanism

Estrogenic compounds reach the spectrum of activities ranging from:

• Full agonist (agonistic in all tissues) such as natural endogenous hormone estradiol
• Mixed/antagonistic agonists (agonists in some networks while antagonists in others) such as tamoxifen (SERM).
• Pure antagonists (antagonists in all tissues) like fulvestrant.

SERMs are known to stimulate estrogenic action in tissues such as liver, bone and cardiovascular systems but are known to block estrogen action in which undesirable stimulation, such as in the breast and uterus. This agonistic or antagonistic activity causes various structural changes of the receptor, which results in activation or suppression of the estrogen target gene. SERM interact with receptor by spreading to cell and binding ER? or ER? subunit, which results in dimerization and structural changes of the receptor. This makes it easier for SERMs to interact with estrogen response elements that lead to the activation of estrogen-induced genes and mediate the effects of estrogen.

SERM's unique feature is selective network and cell activity. There is growing evidence to support that SERM activities are primarily determined by selective recruitment of corepressors and coactivators for ER target genes on specific tissue and cell types. SERMs can affect the stability of coactivator proteins and can also regulate the activity of coactivators through post-translational modifications such as phosphorylation. Multiple growth signal paths, such as HER2, PKC, PI3K, and more, decreased regulation in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by active kinase which also increases its coactivator activity, affects cell growth and ultimately contributes to drug resistance.

ER Ratio? and ER? on the target site may be another way the SERM activity is specified. The high rates of cell proliferation are well correlated with high ER: ER? ratio, but cellular proliferation proliferation is correlated with ER? become dominant over ER? ER ratios in neoplastic and normal breast tissue may be important when considering chemoprevention with SERMs.

When looking at the difference between ER? and ER ?, Enabling Function 1 (AF-1) and AF-2 is important. Together they play an important part in interactions with other co-regulatory proteins that control gene transcription. AF-1 is located in the amino terminal ER and only 20% homolog in ER? and ER? On the other hand, AF-2 is very similar in ER? and ER ?, and only one different amino acid. Studies have shown that by diverting AF-1 regions in ER? and ER ?, that there are specific differences in transcription activity. In general, SERMs can activate some engineering genes through ER? by estrogen receptor element, but not through ER ?. Although, raloxifene and the active form of tamoxifen can stimulate the AF-1 reporter gene set in both ERs? and ER?

Due to the discovery that there are two subtypes of ER, it has been carrying the synthesis of various receptor-specific ligands that may activate or deactivate certain receptors. However, the external form of the resulting complex is the catalyst for converting the response on the target network to the SERM.

X-ray crystallography of estrogen or antiestrogen has shown how ligands reprogrammed receptor complexes to interact with other proteins. The ligand binding domain of the ER shows how the ligand promotes and prevents the binding coactivator based on a form of estrogen or a complex antiestrogen. The various ligands that bind the ER can create a complex spectrum of ER that is completely estrogenic or antiestrogenic at a particular target site. The main result of the ligand binding to the ER is the structural rearrangement of the ligand binding sac, especially in AF-2 from the C-terminal region. The ligand binding to the ER leads to the formation of hydrophobic pockets that regulate cofactors and pharmacological receptors. Proper folding of the ligand binding domain is required for transcriptional activation and ER to interact with a number of coactivators (see figure 4).

Coactivators are not just protein partners linking shared sites within a complex. Coactivators play an active role in modifying complex activities. Post-translational modification of coactivators can produce a dynamic model of steroid hormone action through multiple kinase paths initiated by cell surface growth factor receptors. Under the guidance of many protein experts to form multiprotein co-activator complexes that can interact with phosphorylated ERs at specific gene promoter sites, the core coactivator must first recruit a set of specific cocoactivators. The protein coactivator core is assembled as a coactivated nucleus complex having individual enzymatic activity to methylate or acetate adjacent proteins. The ER substrate or coenzyme A can be polyubiquitinated by multiple reaction cycles or, depending on the protein linkage, they can be activated further or degraded by a 26S proteasome.

Consequently, to have an effective gene transcription programmed and targeted by the structure and status of the ER phosphorylation and coactivator, it is necessary to have a dynamic remodeling process and cycle for the transcription assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome.

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Structure and function

Activity-structure relations

SERM core structure simulate template 17? -estradiol. They have two aromatic rings separated by 1-3 atoms (often a type of stilbene arrangement). Between the two phenyl nuclei, the SERMs typically have a 4-substituted phenyl group which, when bound to the ER, project from the position of the estratriene nucleus so that the helix 12 moves from the receptor opening and blocks the chamber where the coactivating proteins usually bind and cause the agonist ER activity. There are many variations in the SERMs core portion while there is less flexibility with what is tolerated in side chains. SERM can be classified based on its core structure.

first generation triphenylethylenes

The first major structural class of reported SERM type molecules is triphenylethylenes. The stilbene nucleus (similar to nonsteroid estrogen, diethylstilbestrol) essentially mimics estrogen steroids like 17? -estradiol, while the side chain coats with the 11th position of the steroid nucleus (see figure 5). Triphenylethylene derivatives have an additional phenyl group attached to the ethylene bridge group. The 3-position position of the H-bond of phenol is an important requirement for ER binding.

The first drug, clomiphene (2- [4- (2-chloro-1,2-diphenylethenyl) phenoxy -N, N-diethylenotamine, 2-hydroxy-1,2,3-propanetricarboxylate, see figure 6) has chloro-substituted on the ethylene side chain that produces a similar binding affinity as a later tamoxifen drug. Clomifene is a mixture of estrogenic (cis-form) and anti-estrogenic (trans-form) isomers. Cis and trans are defined in terms of the geometric relationship of two unsubstituted phenyl rings. The two clomifene isomers have different profiles, in which the trans form has activity more akin to tamoxifen while the cis form behaves more like 17? -estradiol. Cis is about ten times stronger than trans. However, trans isomers are the most powerful stimulators of epithelial cell hypertrophy because clomifene is antagonistic at low doses and agonistically at high doses. Antagonistic isomers can cause an estrogenic effect of inhibition on uterine and breast cancer, but estrogenic isomers may combine with new receptors to produce effects such as estrogen in bone.

Tamoxifen ((Z) -2- [4- (1,2-diphenylbut-1-enyl) phenoxy] -N, N-dimethyl-ethanamine, see figure 7) has been the treatment of choice for women diagnosed with all stages of breast cancer hormone-responsive, ie ER and/or progesterone-positive breast cancer. In the US, it is also given for prophylactic chemoprevention in women who are identified as a high risk for breast cancer. Tamoxifen is a pure antestrogenic trans-isomer and has a differential action on estrogen target tissue throughout the body. Tamoxifen is selectively antiestrogenic in the breast but resembles estrogen in bone and endometrial cancer. Tamoxifen underwent phase I metabolism in the liver with microsomal cytochrome P450 (CYP) enzymes. The main metabolites of tamoxifen are N-desmethyltamoxifen and 4-hydroxytamoxifen.

The 4-hydroxytamoxifen crystallographic structure interacts with the amino acid ER within the ligand binder domain. The contact between phenolic groups, water molecules, and glutamate and arginine in the receptor (ER ?, Glu 353/Arg 394) resolves in high affinity bonds so that 4-hydroxy tamoxifen, with a phenolic ring resembling the A ring of 17? -estradiol, has a binding affinity comparatively more than 100 times higher than tamoxifen, which has no phenol. If the OH group is removed or its position is changed, its binding affinity decreases.

The triphenylethylene moiety and side chain is needed to bind tamoxifen to the ER, whereas for 4-hydroxytamoxifen, side chain, and phenyl-propene does not appear as an essential structural element for binding ER. The alkalinity and long side chains do not seem to play an important role for tamoxifen binding affinity to the ER or? -ring tamoxifen, but a stilbene tamoxifen portion is required to bind ER. The hydroxyl group is essential for the binding of ER 4-hydroxytamoxifen, and the ethyl tamoxifen side chain stands out from the ligand binder domain of ER.

Some tamoxifen users have suffered from increased rates of uterine cancer, flushes, and thromboembolism. This drug can also cause hepatocarcinoma in mice. This may be due to the ethyl group of stilbene tamoxifen steroids which are subject to alic oxidative activation which causes DNA alkylation and dilution of the strand. This problem is then corrected in toremifene. Tamoxifen is more promiscuous than raloxifene in the target site because of the association between the ER amino acid in Asp-351 and the antiestrogenic side chains of SERM. The side chain for tamoxifen can not neutralize Asp-351, so the allosteric site affects AF-1 at the proximal end of ER. This problem is corrected with second-generation raloxifene drugs.

Toremifene (toremifene citrate, see figure 8), is chemically defined as 2- (p-[(Z) -4-chloro-1,2-diphenyl-1-butenyl] phenoxy) -N, N-dimethylethylamine citrate, is chlorinated derivatives of nonsteroidal triphenylethylene antiestrogens of tamoxifen with chloro substituents on the ethylene side chain which produce a binding affinity similar to tamoxifen. The structure and relationship of toremifene activity are similar to tamoxifen, but have substantial improvements from older drugs in terms of DNA alkylation. The presence of added chlorine atoms reduces the stability of the cation formed from activated allylic metabolites and thereby lowers the alkylation potential, and indeed the toremifene does not exhibit the formation of DNA addition in rat hepatocytes. Toremifene protects against bone loss in mouse models that are ovariectomized and affects clinical bone resorption markers in a manner similar to tamoxifen. Toremifene undergoes phase I metabolism by microsomal cytochrome P450 enzymes, such as tamoxifen, but mainly by CYP3A4 isoforms. Toremifene forms two major metabolites of N-desmethyltoremifene and deaminohydroxy-toremifene (ospemifene) by undergoing N-demethylation and deamination-hydroxylation. N-desmethyltoremifene has the same efficacy as toremifene while 4-hydroxytoremifene has a higher binding affinity to ER than toremifene. 4-hydroxytoremifene has a role similar to 4-hydroxytamoxifen.

second generation Benzothiophenes

Raloxifene ([6-hydroxy-2- (4-hydroxyphenyl) -benzothiophen-3-yl] - [4- [1- (1-piperidyl) ethoxy] phenyl] -methanone; see Figure 9) belongs to the second generation of benzothiophene. It has a high affinity for ER with strong antiestrogenic activity and tissue-specific effects that differ from estradiol. Raloxifene is an ER agonist in the bone and cardiovascular system, but in breast and endometrial tissue it acts as an ER antagonist. It is extensively metabolized by glucuronid conjugation in the gut and therefore has a low bioavailability of only 2% whereas tamoxifen and toremifene are about 100%.

The advantage of raloxifene over triphenylethylene tamoxifen reduces the effect on the uterus. Flexible hinge groups, as well as the antiestrogenic 4-piperidinoetoksik phenyl side chain, are important to minimize the effects of the uterus. Because the elasticity of the side chain may obtain an orthogonal disposition relative to the nucleus so that the raloxifene side-chain amine is 1 ÃÆ'â € | closer than tamoxifens to the Asp-351 amino acid in the ER ligand domain.

The crucial role of intimate relationships between the hydrophobic side chains of raloxifene and the hydrophobic residue of the receptor to alter both the shape and external surface charge of the SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 increased from 2.7 ÃÆ'â € | to 3.5-5 ÃÆ'â € | it led to increased action such as estrogen from raloxifene-ER? complex. When the piperidine raloxifene ring is replaced by cyclohexane, the ligand loses its antiestrogenic properties and becomes a full agonist. The interaction between the SERM antiestrogenic chain side and the Asp-351 amino acid is an important first step in silencing AF-2. This removes the 12 helix away from the ligand-binding sac thus preventing the coactivator from binding to the complex SERM-ER.

Third generation

Third generation compounds do not show uterine stimulation, increased potential, no significant increase in hot flushes or even combinations of these positive attributes.

Modification of the first dihydronapthalene SERM, nafoxidine (see figure 10), which is a clinical candidate for the treatment of breast cancer but has adverse effects including severe phototoxicity, resulting in lasofoxifene (5R, 6S) -6-phenyl-5- [4- (2-pyrrolidin- 1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol; see figure 11). Nafoxidine has all three phenyls constrained in coplanar settings such as tamoxifen. But with hydrogenation, the double bond of naphoxide is reduced, and the two phenyls are cis-oriented. The amine-bearing side chains can then adopt axial conformations and place these groups orthogonally into the core areas, such as ralophoxifene and other uterotropic SERMs.

Lasofoxifen is one of the most powerful SERMs reported in the protection against bone loss and cholesterol reduction. The excellent oral potency of lasofoxifene has been attributed to the reduction of gut glucuronate from phenol. Unlike raloxifene, lasofoxifene meets the requirements of pharmacofora models that predict resistance to glutonidation of the intestinal wall. The structural requirement is a non-planar topology with a steric mass close to the plane of the arched bicyclic aromatic system. The interaction between ER and lasofoxifene is consistent with the common features of the introduction of SERM-ER. The flexible large-sided flexible side-toothloxenes end in the pyrrolidine head group and the yarn outward to the protein surface, where it interferes directly with the helix position of AF-2. Salt bridges are formed between lasofoxifene and Asp-351. Penetration of charge in this region of ER can explain some of the antiestrogenic effects provided by lasofoxifene.

The indole system has functioned as a core unit in the SERMs, and when the amine is attached to indole with benzyloxyethyl, the resulting compound proves to have no preclinical uterine activity while sparing the mouse bone with full effectiveness at low doses. Bazedoxifene (1H-indo-5-ol, 1 - [[4- [2 (hexahydro-1H-azepin-1-yl) ethoxy] methyl] 2 - (- 4-hydroxyphenlyl) -3-methyl; acetic acid) is one of these compounds. The core binding domain consists of 2-phenyl-3-methyl indole and a hexamethylenamine ring in the affective region of the side chain. It is metabolized by glucuronidation, with an absolute bioavailability of 6.2%, 3 times higher than raloxifene. It has an agonistic effect on bone and lipid metabolism but not on the endometrium of the breast and uterus. It is well tolerated and does not show an increased incidence of hot flush, uterine hypertrophy or breast pain.

Ospemifene (Z-2- (4- (4-chloro-1,2-diphenyl-but-1-enyl) phenoxy) see ethanol 13) is a known triphenylethylene and metabolite of toremifene. It's structurally very similar to tamoxifen and toremifene. Ospemifene has no ethoxy 2- (dimethylamino) group as tamoxifen. The study of activity-structure relationships encouraged that by removing the tamoxifen agonist activity group in the uterus significantly reduced, but not in the bone and cardiovascular system. Preclinical and clinical data suggest that ospemifene is well tolerated without major side effects. The benefits that ospemifene may have over other SERMs are the neutral effects on hot flushes and the effects of ER-agonists on the vagina, improving the symptoms of vaginal dryness.

Binding mode

SERMs are known to display four different binding modes with ER. One such feature is the strong hydrogen bond between the ligand and ER's Arg-394 and the coating Glu-353, the A-ring pocket "and helps the ligand to remain in the ER ligature pocket.It is unlike the 17? - hydrogen-bound estradiol -The 524 in the "D-ring" pockets. Another distinctive feature for ligand-binding binds is that the almost planar "core" structure usually consists of a heterocycle biaryl, equivalent to A-ring and B-ring 17? -estradiol (see figure 14), to a suitable binding site, a large side chain of the biaryl structure, analogous to the B-ring 17 -estradiol and finally the second side group representing C- and D-rings equivalent and usually aromatic, filling the residual volume of the ligand binding sac.

A small difference between the two subtypes of ER has been used to develop selective subtype ER modulators, but the high similarity between the two receptors makes development particularly challenging. Amino acids in ligand binding domains differ in two positions, Leu-384 and Met-421 in ER? and Met-336 and Ile-373 in ER ?, but they have the same hydrophobicity and volume. However, the shape and the rotational barrier of amino acid residues are not the same, which leads to differentiate? - and? -face cavity binding between ER? and ER? This causes ER? -preferential-binding substitution of parallel ligand facing down Met-336 while parallel ligand face up facing upwards-336 more likely to bind ER ?. Another difference is in Val-392 in ER ?, which was replaced by Met-344 in ER ?. The pocket volume that binds ER is slightly smaller and the shape is slightly different from the ER's. Many ER-select ligands have most planar settings as ER binding cavities? slightly more narrow than ER, however, this alone leads to simple selectivity. To achieve strong selectivity, ligands should place substituents very close to one or more amino acid differences between ERs? and ER? to create a strong repulsive force against other subtype recipes. In addition, the ligand structure must be rigid. Disgusting interactions can lead to changes in ligand conformation and, therefore, create alternative binding modes.

First generation triphenylethylenes

Tamoxifen is altered by the P450 liver cytochrome into 4-hydroxytamoxifen and is a more selective antagonist of ER? subtype of ER ?. 4-hydroxytamoxifen binds to ERs in the same binding bag that recognizes 17? -estradiol. Recognition of 4-hydroxytamoxifen receptors appears to be controlled by two structural features of 4-hydroxytamoxifen, phenolic ring A, and large side chains. Phenolic A ring forms hydrogen bonds to the side group of Arg-394 ER, Glu-354 and into structurally structured water. The large side chains, protruding from the binding cavity, replace the 12 helix of the ligand pocket to cover part of the pocket that binds the coactivator. The complex formation of ER-4-hydroxytamoxifen recruits protein corepressors. This leads to decreased DNA synthesis and inhibition of estrogen activity. Clomifene and torimefene produce a binding affinity that is similar to tamoxifen. Thus, these two drugs are more selective antagonists of ER? subtype of ER ?.

second generation Benzothiophenes

Raloxifene, like 4-hydroxytamoxifen, binds to ER? with a hydroxyl group of phenolic "A ring" (see figure 15) by hydrogen bonding with Arg-394 and Glu-353. In addition to this bond, raloxifene forms the second hydrogen bond to the ER via the side group His-524 because of the presence of a second hydroxyl group in "D ring" (see figure 15). This hydrogen bond is also not like between 17? -estradiol and His-524, because the His-524 imidazole ring is rotated to counteract the oxygen position difference in raloxifene and at 17? -estradiol. Just like in 4-hydroxytamoxifen, a large side-chain of raloxifene replaces helix 12.

Third generation

Interaction of Lasofoksifen with ER? is the distinctive feature between SERM-ER? such as a near-planar topology (tetrahydronapthalene carbocycle), hydrogen bonds with Arg-394 and Glu-353 and a phoflet chain of weldofoxifene filling the C ring and the D-ring volume of the ligand binding pouch. Lasofoxifen diverts helix 12 and prevents the binding of the coactivator protein with the LXXLL motif. This is achieved by the occupied weldofoxifene normally occupied by the Leu-540 side group and modulating the conformation of helical residues 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with the position of helix 12 by the ethyl pyrrolidine drug group. In vitro studies show that bazedoxifene is competitively blocking 17? -estradiol by high binding and similar for both ER? and ER? Bazedoxifenes main binding domains consist of 2-phenyl-3-methylindole and hexamethylenamine ring in the side-affected area.

Ospemifene is an oxidative-defined metabolite of toremifene because it has a binding similar to ER as toremifene and tamoxifen. Competitive bond for ER? and ER? of the three 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and 4-hydroxy-hydroxy metholites, the side chain of the Ospemifene carboxylic acid is at least as high as the parent compound.

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History

The invention of SERMs resulted from efforts to develop new contraceptives. The time line when the SERM comes in the market is shown in Figure 1. Clomifene and tamoxifen prevent conception in mice but do otherwise in humans. Clomifene succeeded in inducing ovulation in subfertile women and on February 1, 1967, was approved in the US for the treatment of ovulatory dysfunction in women trying to conceive. Toxicological problems prevent long-term clomiphene use and further drug development for other potential applications such as treatment and prevention of breast cancer.

It was ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer. The discovery in 1987 that SERMs tamoxifen and raloxifene, then considered antiestrogens due to antagonistic effects in breast tissue, showed an estrogenic effect in preventing bone loss in ovariectomized rats having a profound effect on our understanding of the functioning of estrogen receptors and nuclear receptors. generally. The term SERM is introduced to describe compounds that have a combination of estrogen agonists, partial agonists, or antagonistic activity depending on the tissue. Toremifene has been shown to be compatible with tamoxifen, and in 1996 was approved for use in the treatment of breast cancer in postmenopausal women.

Raloxifene initially failed as a breast cancer drug because of its poor performance compared to tamoxifen in the laboratory but the estrogenic effects of raloxifene on bone led to rediscovery and consent in 1997. It was approved for the prevention and treatment of osteoporosis and was the first clinically available SERM to prevent osteoporosis and breast cancer. Ospemifene is approved on February 26, 2013, for the treatment of moderate to severe dyspareunia, which is a symptom, due to menopause, vulvar and vaginal atrophy. Combination therapy with conjugated estrogens and bazedoxifene serm, has been approved on 3 October 2013, for the treatment of vasomotor symptoms associated with menopause. Bazedoxifene is also used in the prevention of postmenopausal osteoporosis. Stronger SERM search with better bone efficacy and bioavailability than raloxifene led to the discovery of lasofoxifene. Although lasofoxifene was approved in 2009, it was not marketed for three years after approval, so the marketing authorization for it has ended. In Europe, bazedoxifene is indicated for the treatment of osteoporosis in postmenopausal women with an increased risk of fracture while in India ormeloxifene has been used for dysfunctional uterine bleeding and birth control.

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See also

• Estrogen deprivation therapy
• List of selective estrogen receptor modulators
• Selective estrogen receptor degrader
• Selective receptor modulators
• Cancer treatment development time line

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References

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External links

• AACR Cancer Concepts Factsheet on SERMs
• STAR: comparison of head-to-head tamoxifen and raloxifene as breast cancer prevention
• Femarelle's official site
• The official site of Raloxifene (Evista)

Source of the article : Wikipedia