Selective glucocorticoid receptor agonist
Encyclopedia
A selective glucocorticoid receptor agonist (SEGRA), sometimes called a dissociated glucocorticoid receptor agonist (DIGRA), is a type of experimental drug that is designed to share many of the desirable anti-inflammatory
and immunosuppressive properties of classical glucocorticoid
drugs but with fewer side effects such as skin atrophy
. , Phase II clinical trial
s with the SEGRA mapracorat
investigating the topical
treatment of atopic dermatitis
and inflammation following cataract surgery
have been completed, but no results are available. Such trials attempt to determine whether the theoretical concept translates into an actual clinical benefit.
s with SEGRA-like properties were already discovered in the late 1990s. During the 2000s, many potential SEGRAs were synthesized, most of them having non-steroidal structures. Compounds were investigated in cellular models, which established that these molecules bind to the glucocorticoid receptor
with an affinity similar to dexamethasone
, a potent glucocorticoid, and that they are able to repress the production of inflammatory mediators such as interleukin 6
and prostaglandin E2. Studies in mice showed that a topically administered SEGRA inhibited peroxidase
activity and formation of oedema, both indicators of anti-inflammatory activity, comparably to prednisolone
. Skin atrophy in rats was significantly less pronounced than under prednisolone in the same study, and metabolic effects like weight gain or increase of blood glucose were practically inexistent.
Phase II clinical trials with one of the candidate compounds, mapracorat (code names BOL-303242-X and ZK 245186), 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
. A Phase III trial started in November 2010, evaluating an ophthalmic
suspension
for the treatment of inflammation following cataract surgery, conducted by Bausch & Lomb
.
(GR). In contrast to glucocorticoids, which activate the GR to work through two signal transduction
pathways, SEGRAs activate the GR in such a way that it only operates through one of the two possible pathways.
In the absence of glucocorticoids, the GR resides in the cytosol
in an inactive state complexed with heat shock protein
s (HSPs). Binding of glucocorticoids to the GR activates the receptor by causing dissociation of the bound HSPs. The activated GR can then regulate gene expression via one of two pathways:
Hence the anti-inflammatory effects of glucocorticoids results from both transactivation and transrepression. In contrast, studies in rats have shown that most of the side-effects of glucocorticoids, such as diabetogenic activity, osteoporosis
, as well as skin atrophy, are caused by transactivation. A selective glucocorticoid that is able to transrepress without transactivation should preserve many of the desirable therapeutic anti-inflammatory effects and minimize undesired side effects.
Strong evidence that transpression alone is 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. At same time, this mutation did not interfere with transrepression. While GR is essential for survival, these mice are still viable. However, when these mice were treated with the synthetic glucocorticoid dexamethasone, there was no elevation of glucose. At the same time, these dexamethsone treated mice were resistant to inflammatory stimulus. 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, SEGRAs bind to and activate GR. However in contrast to glucocorticoids, SEGRAs selectively activate the GR such that they more strongly transrepress than transactivate. This should result in fewer side effecs.
Inflammatory diseases of the eye are also a potential application because corticoids can promote glaucoma
, cataract
, and eye infections. It remains to be seen whether selective receptor agonists cause significantly less side-effects than classical corticoids in clinical application.
The atrophic effects of glucocorticoids are not always a disadvantage. The treatment of hyperproliferative
diseases like psoriasis
makes use of this property. SEGRAs would likely be less effective in such conditions.
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 and 55D1E1. 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.
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and immunosuppressive properties of classical glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
drugs but with fewer side effects such as skin atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
. , Phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s with the SEGRA mapracorat
Mapracorat
Mapracorat is an anti-inflammatory drug belonging to the experimental class of selective glucocorticoid receptor agonists . It is in clinical trials for the topical treatment of atopic dermatitis, inflammation following cataract surgery, and allergic conjunctivitis...
investigating the topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...
treatment of atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...
and inflammation following cataract surgery
Cataract surgery
Cataract surgery is the removal of the natural lens of the eye that has developed an opacification, which is referred to as a cataract. Metabolic changes of the crystalline lens fibers over time lead to the development of the cataract and loss of transparency, causing impairment or loss of vision...
have been completed, but no results are available. Such trials attempt to determine whether the theoretical concept translates into an actual clinical benefit.
History
Synthetic steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s with SEGRA-like properties were already discovered in the late 1990s. During the 2000s, many potential SEGRAs were synthesized, most of them having non-steroidal structures. Compounds were investigated in cellular models, which established that these molecules bind to the glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
with an affinity similar to dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
, a potent glucocorticoid, and that they are able to repress the production of inflammatory mediators such as interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
and prostaglandin E2. Studies in mice showed that a topically administered SEGRA inhibited peroxidase
Peroxidase
Peroxidases are a large family of enzymes that typically catalyze a reaction of the form:For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides...
activity and formation of oedema, both indicators of anti-inflammatory activity, comparably to prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
. Skin atrophy in rats was significantly less pronounced than under prednisolone in the same study, and metabolic effects like weight gain or increase of blood glucose were practically inexistent.
Phase II clinical trials with one of the candidate compounds, mapracorat (code names BOL-303242-X and ZK 245186), 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
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
. A Phase III trial started in November 2010, evaluating an ophthalmic
Ophthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...
suspension
Suspension
Suspension may refer to:In science and engineering:*Suspension , in mathematics*Suspension , in mathematics*Suspension , mixture of two chemicals with the property that one does not rapidly settle out...
for the treatment of inflammation following cataract surgery, conducted by Bausch & Lomb
Bausch & Lomb
Bausch & Lomb, an American company based in Rochester, New York, is one of the world's leading suppliers of eye health products, such as contact lenses and lens care products today. In addition to this main activity, in recent years the area of medical technology has been developed...
.
Mechanism of action
Both non-selective glucocorticoids and selective glucocorticoid receptor agonists work by binding to and activating the glucocorticoid receptorGlucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
(GR). In contrast to glucocorticoids, which activate the GR to work through two signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways, SEGRAs activate the GR in such a way that it only operates through one of the two possible pathways.
In the absence of glucocorticoids, the GR resides in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
in an inactive state complexed with heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s (HSPs). Binding of glucocorticoids to the GR activates the receptor by causing dissociation of the bound HSPs. The activated GR can then regulate gene expression via one of two pathways:
- The first (direct) pathway is called transactivationTransactivationIn molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
whereby the activated GR dimerProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
izes, is translocatedProtein targetingProtein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
into the nucleusCell nucleusIn cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and binds to specific sequences of DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
called glucocorticoid response elementsHormone response elementA hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
. The GR/DNA complex recruits other proteins which transcribe downstream DNA into mRNAMessenger RNAMessenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
and eventually proteinProteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. Examples of glucocorticoid responsive genes include those that encode annexin A1Annexin A1Annexin A1 also known as lipocortin I is a protein that in humans is encoded by the ANXA1 gene.- Function :Annexin I belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the...
, angiotensin-converting enzymeAngiotensin-converting enzymeAngiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
, neutral endopeptidase and other anti-inflammatory proteins.
- The second (indirect) pathway is called transrepressionTransrepressionIn the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction...
, in which activated monomerMonomerA monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
ic GR binds to other transcription factors such as NF-κB and AP-1AP-1 (transcription factor)In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
and prevents these from up-regulating the expression of their target genes. These target genes encode proteins such as cyclooxygenaseCyclooxygenaseCyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
, NO synthase, phospholipase A2Phospholipase A2Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
, tumor necrosis factorTumor necrosis factorTumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
, transforming growth factor beta, ICAM-1ICAM-1ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system...
, and a number of other pro-inflammatory proteins.
Hence the anti-inflammatory effects of glucocorticoids results from both transactivation and transrepression. In contrast, studies in rats have shown that most of the side-effects of glucocorticoids, such as diabetogenic activity, osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, as well as skin atrophy, are caused by transactivation. A selective glucocorticoid that is able to transrepress without transactivation should preserve many of the desirable therapeutic anti-inflammatory effects and minimize undesired side effects.
Strong evidence that transpression alone is sufficient for an anti-inflammatory response was provided by introducing a point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
in the GR of mice that prevented GR from dimerizing and binding to DNA and thereby blocking transactivation. At same time, this mutation did not interfere with transrepression. While GR is essential for survival, these mice are still viable. However, when these mice were treated with the synthetic glucocorticoid dexamethasone, there was no elevation of glucose. At the same time, these dexamethsone treated mice were resistant to inflammatory stimulus. 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, SEGRAs bind to and activate GR. However in contrast to glucocorticoids, SEGRAs selectively activate the GR such that they more strongly transrepress than transactivate. This should result in fewer side effecs.
Potential applications
In chronic inflammatory diseases of the skin like atopic dermatitis, the side-effects of corticoids are problematic because of the necessary long-term treatment. Therefore, SEGRAs are being investigated as an alternative topical treatment. Systemic long-term treatment of inflammations with corticoids is particularly liable to cause metabolic side-effects, which makes the development of oral SEGRAs an interesting goal.Inflammatory diseases of the eye are also a potential application because corticoids can promote glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
, and eye infections. It remains to be seen whether selective receptor agonists cause significantly less side-effects than classical corticoids in clinical application.
The atrophic effects of glucocorticoids are not always a disadvantage. The treatment of hyperproliferative
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
diseases like psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
makes use of this property. SEGRAs would likely be less effective in such conditions.
Chemistry
Early SEGRAs were synthetic steroids. An example is RU 24858, one of the first compounds of this type to be published. 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.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 and 55D1E1. The bulky, bicyclic aromatic substituents (R1 and R2) account for the structural similarity to corticoids. The R conformation of the asymmetric carbon
Asymmetric carbon
An asymmetric carbon atom is a carbon atom that is attached to four different types of atom or four different groups of atoms. Knowing the number of asymmetric carbon atoms, one can calculate the maximum possible number of stereoisomers for any given molecule as follows:As an example, malic acid...
atom seems to be essential for GR affinity.
See also
- Selective receptor modulatorSelective receptor modulatorIn the field of pharmacology, a selective receptor modulator or SRM is a type of drug that has different effects in different tissues. A SRM may behave as an agonist in some tissues while as an antagonist in others. Hence selective receptor modulators are sometimes referred to as tissue selective...
- Selective androgen receptor modulatorSelective androgen receptor modulatorSelective androgen receptor modulators or SARMs are a novel class of androgen receptor ligands. They are intended to have the same kind of effects as androgenic drugs like anabolic steroids but be much more selective in...
- Selective estrogen receptor modulatorSelective estrogen receptor modulatorSelective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
- Selective progesterone receptor modulatorSelective progesterone receptor modulatorA selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...