Selective glucocorticoid receptor modulator

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Selective glucocorticoid receptor modulator
Drug class
Mapracorat skeletal.svg
Chemical structure of mapracorat, one of the furthest developed SEGRAs. [1]
Class identifiers
Synonyms SEGRM; SEGRA; SEGRAM; DIGRA
UsePotentially atopic dermatitis, glaucoma, cataract, eye infections, and others
Biological target Glucocorticoid receptor
Chemical class Steroidal; nonsteroidal
Legal status
In Wikidata

Selective glucocorticoid receptor modulators (SEGRMs) and selective glucocorticoid receptor agonists (SEGRAs) formerly known as dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs but with fewer side effects such as skin atrophy. Although preclinical evidence on SEGRAMs’ anti-inflammatory effects are culminating, [2] currently, the efficacy of these SEGRAMs on cancer are largely unknown.

Contents

Selective glucocorticoid receptor agonists (SEGRAs) are historically and typically steroidal in structure while selective glucocorticoid receptor modulators (SEGRMs) are typically nonsteroidal. The combined abbreviation of selective glucocorticoid receptor agonist and modulator is SEGRAM. [2] A number of such ligands have been developed and are being evaluated in preclinical and clinical testing.

SEGRAMs achieve their selectivity by triggering only a subset the glucocorticoid receptor mechanisms of action. [3] [4]

History

Synthetic steroids with SEGRA-like properties were already discovered in the late 1990s. [5] During the 2000s, many potential SEGRAMs were synthesized, most of them having nonsteroidal structures. In in vitro studies in cellular models these SEGRAM molecules bind to the glucocorticoid receptor with an affinity similar to dexamethasone, a potent glucocorticoid, and with an ability to repress the production of inflammatory mediators such as interleukin 6 and prostaglandin E2. [6] Moreover, in vitro a particular SEGRAM can promote apoptosis in prostate cancer [7] and leukemia. [8]

In vivo studies in mice and rats showed that a topically administered SEGRAM inhibited peroxidase activity and formation of oedema, both indicators of anti-inflammatory activity, comparably to prednisolone. Systemic administration in mice or rats indicate that SEGRAMs can diminish acute infections, rheumatoid arthritis, asthma and colitis. [2] In vivo evidence on whether particular SEGRAMs can elicit similar effects than classic glucocorticoid in cancer pathologies is currently lacking. Current preclinical tests show that the SEGRAMs available so far would elicit fewer side effect or at least less grave side effects than classic glucocorticoids would. [2] For example, skin atrophy in rats was significantly less pronounced than under prednisolone in a study using the SEGRAM Mapracorat, and metabolic effects like weight gain or increase of blood glucose were practically inexistent. [9]

Mechanism of action

The benzopyranoquinoline A 276575, an example of a SEGRA with a more corticosteroid-like structure A 276575 structure.svg
The benzopyranoquinoline A 276575, an example of a SEGRA with a more corticosteroid-like structure

Both non-selective glucocorticoids and selective glucocorticoid receptor agonists work by binding to and activating the glucocorticoid receptor (GR). In contrast to glucocorticoids, which activate the GR to work through (at least) two signal transduction pathways, [10] SEGRAMs activate the GR in such a way that it only operates through one of the two main possible pathways. [11]

In the absence of glucocorticoids, the GR resides in the cytosol in an inactive state complexed with heat shock proteins (HSPs) and immunophilins. Binding of glucocorticoids to the GR activates the receptor by causing a conformational change in the GR and thus a dissociation of the bound HSPs. The activated GR can then regulate gene expression via one of two pathways: [10]

Transactivation
The first (direct) pathway is called transactivation whereby the activated GR dimerizes, is translocated into the nucleus and binds to specific sequences of DNA called glucocorticoid response elements (GREs). The GR/DNA complex recruits other proteins which transcribe downstream DNA into mRNA and eventually protein. Examples of glucocorticoid-responsive genes include those that encode annexin A1, TSC22D3 (also known as GILZ), angiotensin-converting enzyme, neutral endopeptidase and other anti-inflammatory proteins.
Transrepression
The second (indirect) pathway is called transrepression, in which activated monomeric GR binds to other transcription factors such as NF-κB and AP-1 and prevents these from up-regulating the expression of their target genes. These target genes encode proteins such as cyclooxygenase, NO synthase, phospholipase A2, tumor necrosis factor, transforming growth factor beta, ICAM-1, and a number of other pro-inflammatory proteins.
Simplified overview of the mechanism of action of a classical glucocorticoid vs the mechanism of action of a SEGRAM SEGRAM basic mechanism.tif
Simplified overview of the mechanism of action of a classical glucocorticoid vs the mechanism of action of a SEGRAM

Hence the anti-inflammatory effects of glucocorticoids results from both transactivation and transrepression. In contrast, studies in rats and mice have shown that most of the side effects of glucocorticoids, such as diabetogenic activity, osteoporosis, as well as skin atrophy, are mainly caused by transactivation. [9] [12] [13] A selective glucocorticoid that is able to transrepress without transactivation should preserve many of the desirable therapeutic anti-inflammatory effects and minimize these particular undesired side effects. [11]

Initial evidence that transpression alone can be sufficient for an anti-inflammatory response was provided by introducing a point mutation in the GR of mice that prevented GR from dimerizing and binding to DNA and thereby blocking transactivation. [14] [15] At the same time, this mutation did not interfere with transrepression. While GR is essential for survival, these mice are still viable. [14] However, when these mice were treated with the synthetic glucocorticoid dexamethasone, there was no elevation of glucose. These dexamethasone-treated mice were resistant to an inflammatory stimulus. [15] Hence, these mice were responsive to the anti-inflammatory effects of dexamethasone but were resistant to at least some of the side effects.

Just like glucocorticoids, SEGRAMs bind to and activate GR. However, in contrast to glucocorticoids, SEGRAMs selectively activate the GR in such a way that they yield an improved therapeutic benefit. Generally, for specific inflammation-based diseases, SEGRAMs should more strongly transrepress than transactivate, or better yet solely transrepress and fail to transactivate. This type of selective GR activation should result in fewer side effects than the expected side effects that appear with a chronic treatment with classic glucocorticoids. [16]

Clinical trials

Phase II clinical trials with one of the candidate compounds, mapracorat (code names BOL-303242-X and ZK 245186 [17] ), started in summer 2009. One was a double blind dose finding study for an ointment against atopic dermatitis conducted by Intendis, a part of Bayer HealthCare Pharmaceuticals specialized on dermatology. [18] A Phase III trial started in November 2010, evaluating an ophthalmic suspension for the treatment of inflammation following cataract surgery, conducted by Bausch & Lomb. [19]

A phase II trial with another dissociated glucocorticoid fosdagrocorat (PF-04171327) (a phosphate ester prodrug of dagrocorat (PF-00251802) [20] [21] ) for rheumatoid arthritis was started in 2011 by Pfizer. [22]

The results of these clinical trials have not yet been disclosed and no SEGRAM has as yet been approved for clinical use.

Potential applications

In chronic inflammatory diseases like atopic dermatitis (skin), rheumatoid arthritis (joints),..., the side effects of corticosteroids are problematic because of the necessary long-term treatment. Therefore, SEGRAMs are being investigated as an alternative topical treatment. Systemic long-term treatment of inflammations with corticosteroids is particularly liable to cause metabolic side-effects, which makes the development of oral SEGRAMs an interesting goal. [23] It remains to be seen whether selective receptor agonists or modulators indeed cause significantly less side-effects than classical corticoids in clinical applications.

Beneficial atrophic effects

Of note, the atrophic effects of glucocorticoids are not always a disadvantage. The treatment of hyperproliferative diseases like psoriasis makes use of this property. [24] SEGRAMs would likely be less effective in such conditions. Recent advances have shown that the former striving towards a total separation of GR transrepression and transactivation by using SEGRAMs deserves to be nuanced as the anti-inflammatory genes stimulated by GR transactivation, such as GILZ and DUSP1, do seem to play an important role. [25] [26] Nevertheless, the more selective nature of these SEGRAMs would still reduce the number of GR-mediated side effects, and deserves further clinical testing.

Chemistry

RU 24858, a SEGRA with steroid structure RU 24858 skeletal.svg
RU 24858, a SEGRA with steroid structure
An octahydrophenanthrene-2,7-diol derivative with SEGRA properties Octahydrophenanthrene-2,7-diol SEGRA.svg
An octahydrophenanthrene-2,7-diol derivative with SEGRA properties

Early SEGRAs were synthetic steroids. An example is RU 24858, one of the first compounds of this type to be published. [5] Many newer SEGRAs have a different framework, although the similarity to steroids can still be seen in molecules like the benzopyranoquinoline A 276575 or in octahydrophenanthrene-2,7-diol derivatives. All of these compounds have been shown to exhibit SEGRA properties in cellular or in animal models. [3]

Mapracorat is one of a number of trifluoropropanolamines and -amides which are less obviously steroid-like in structure. Other typical examples of this group are ZK 216348 [9] and 55D1E1. [4] The bulky, bicyclic aromatic substituents (R1 and R2) account for the structural similarity to corticoids. The R conformation of the asymmetric carbon atom seems to be essential for GR affinity. [9]

Trifluoroisopropanolamine SEGRA.svg

List of SEGRMs

See also

Related Research Articles

<span class="mw-page-title-main">Corticosteroid</span> Class of steroid hormones

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

<span class="mw-page-title-main">Dexamethasone</span> Corticosteroid medication

Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cava syndrome, and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it may be used in combination with a mineralocorticoid medication such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, as an injection into a vein, as a topical cream or ointment for the skin or as a topical ophthalmic solution to the eye. The effects of dexamethasone are frequently seen within a day and last for about three days.

<span class="mw-page-title-main">Glucocorticoid</span> Class of corticosteroids

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.

<span class="mw-page-title-main">Methylprednisolone</span> Corticosteroid medication

Methylprednisolone is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.

<span class="mw-page-title-main">Selective progesterone receptor modulator</span> Drug affecting hormone receptors

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 and full antagonists 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.

<span class="mw-page-title-main">Glucocorticoid receptor</span> Receptor to which cortisol and other glucocorticoids bind

The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind.

A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents.

In the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction. Since this repression occurs between two different protein molecules (intermolecular), it is referred to as a trans-acting process.

<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">Loteprednol</span> Pharmaceutical drug

Loteprednol is a topical corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax and Loterex.

<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.

<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">Mapracorat</span> Type of selective glucocorticoid receptor agonist

Mapracorat is an anti-inflammatory drug belonging to the experimental class of selective glucocorticoid receptor agonists (SEGRAs). It is in clinical trials for the topical treatment of atopic dermatitis, inflammation following cataract surgery, and allergic conjunctivitis. Preliminary investigation for the treatment of keratoconjunctivitis sicca has been conducted in cellular models.

<span class="mw-page-title-main">AZD-5423</span> Chemical compound

AZD-5423 is a nonsteroidal glucocorticoid and phase II experimental drug being developed by AstraZeneca and disclosed at the spring 2013 American Chemical Society meeting in New Orleans to treat respiratory diseases and in particular chronic obstructive pulmonary disease.

Membrane glucocorticoid receptors (mGRs) are a group of receptors which bind and are activated by glucocorticoids such as cortisol and corticosterone, as well as certain exogenous glucocorticoids such as dexamethasone. Unlike the classical nuclear glucocorticoid receptor (GR), which mediates its effects via genomic mechanisms, mGRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. The identities of the mGRs have yet to be fully elucidated, but are thought to include membrane-associated classical GRs as well as yet-to-be-characterized G protein-coupled receptors (GPCRs). Rapid effects of dexamethasone were found not be reversed by the GR antagonist mifepristone, indicating additional receptors besides just the classical GR.

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

Vosilasarm, also known by the development codes RAD140 and EP0062 and by the black-market name Testolone or Testalone, is a selective androgen receptor modulator (SARM) which is under development for the treatment of hormone-sensitive breast cancer. It is specifically under development for the treatment of androgen receptor-positive, estrogen receptor-negative, HER2-negative advanced breast cancer. Vosilasarm was also previously under development for the treatment of sarcopenia, osteoporosis, and weight loss due to cancer cachexia, but development for these indications was discontinued. The drug is taken by mouth.

<span class="mw-page-title-main">MK-0773</span> Abandoned drug

MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia in women and men. Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter. MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.

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

Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy. It is taken by mouth. It is a dual atypical glucocorticoid and antimineralocorticoid.

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

Dagrocorat is a nonsteroidal but steroid-like selective glucocorticoid receptor modulator (SGRM) which was under development for the treatment of rheumatoid arthritis but was never marketed. It is described as a partial agonist and "dissociable" agonist of the glucocorticoid receptor. The drug reached phase I clinical trials prior to the discontinuation of its development. The C2α dihydrogen phosphate ester of dagrocorat, fosdagrocorat, was also under investigation, but its development was terminated as well.

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

Fosdagrocorat is a nonsteroidal but steroid-like selective glucocorticoid receptor modulator (SGRM) which was under development for the treatment of rheumatoid arthritis but was never marketed. It is the C2 dihydrogen phosphate ester of dagrocorat, and acts as a prodrug of dagrocorat with improved pharmacokinetics. The drug reached phase II clinical trials prior to the discontinuation of its development.

References

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  18. ↑ Clinical trial number NCT00944632 for "Dose Escalation of Different Concentrations of ZK 245186 in Atopic Dermatitis" at ClinicalTrials.gov
  19. ↑ Clinical trial number NCT01230125 for "Mapracorat Ophthalmic Suspension for the Treatment of Ocular Inflammation Following Cataract Surgery" at ClinicalTrials.gov
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