View source for Selective glucocorticoid receptor modulator

{{Short description|Class of experimental drugs}}
{{Redirect|DIGRA|the research association also known as DiGRA|Digital Games Research Association|other uses|Digra (disambiguation){{!}}Digra}}
{{redirect-distinguish|SEGRAM|Seagram (disambiguation){{!}}Seagram}}
{{Infobox drug class
| Image = Mapracorat skeletal.svg
| ImageClass = skin-invert-image
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| Caption = [[Chemical structure]] of [[mapracorat]], one of the furthest developed SEGRAs.<ref name="Prous" />
| Width = 250px
| Synonyms = SEGRM; SEGRA; SEGRAM; DIGRA
<!-- Class identifiers -->
| Use = Potentially [[atopic dermatitis]], [[glaucoma]], [[cataract]], [[eye infection]]s, and others
| ATC_prefix =
| Biological_target = [[Glucocorticoid receptor]]
| Chemical_class = [[Steroid]]al; [[nonsteroidal]]
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| Drugs.com =
| Consumer_Reports =
| medicinenet =
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'''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,<ref name="Sundahl P&T 2015"/> currently, the efficacy of these SEGRAMs on cancer are largely unknown.
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'''.<ref name="Sundahl P&T 2015"/>  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.<ref name="Robinson" /><ref name="Biggadike" />
== History ==
Synthetic [[steroid]]s with SEGRA-like properties were already discovered in the late 1990s.<ref name="Vayssiere" /> 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]].<ref name="A 276575" />  Moreover, ''in vitro'' a particular SEGRAM can promote apoptosis in [[prostate cancer]]<ref name="Yemelyanov 2008"/> and [[leukemia]].<ref name="Lesovaya 2011"/>
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]].<ref name="Sundahl P&T 2015"/> ''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.<ref name="Sundahl P&T 2015"/> 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.<ref name="ZK 209614" />
== Mechanism of action ==
[[File:A 276575 structure.svg|class=skin-invert-image|thumb|The benzopyranoquinoline A 276575, an example of a SEGRA with a more [[corticosteroid]]-like structure<ref name="A 276575" />]]
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,<ref name="pmid16236742" /> SEGRAMs activate the GR in such a way that it only operates through one of the two main possible pathways.<ref name="pmid17622575" />
In the absence of glucocorticoids, the GR resides in the [[cytosol]] in an inactive state complexed with [[heat shock protein]]s (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:<ref name="pmid16236742" />
;Transactivation: The first (direct) pathway is called [[transactivation]] whereby the activated GR [[protein dimer|dimer]]izes, is [[protein targeting|translocated]] into the [[cell nucleus|nucleus]] and binds to specific sequences of [[DNA]] called [[hormone response element|glucocorticoid response elements]] (GREs).  The GR/DNA complex recruits other proteins which transcribe downstream DNA into [[messenger RNA|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 [[monomer]]ic GR binds to other transcription factors such as [[NF-κB]] and [[AP-1 (transcription factor)|AP-1]] and prevents these from up-regulating the expression of their target genes.  These target genes encode proteins such as [[cyclooxygenase]], [[Nitric oxide synthase|NO synthase]], [[phospholipase A2]], [[tumor necrosis factor]], [[transforming growth factor beta]], [[ICAM-1]], and a number of other pro-inflammatory proteins.
[[File:SEGRAM basic mechanism.tif.jpg|class=skin-invert-image|thumb|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.<ref name="ZK 209614" /><ref name="OEAZ" /><ref name="Coghlan" />  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.<ref name="pmid17622575" />
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.<ref name="pmid9604929" /><ref name="pmid11076028" />  At the same time, this mutation did not interfere with transrepression.  While GR is essential for survival, these mice are still viable.<ref name="pmid9604929"/>  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.<ref name="pmid11076028"/>  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.<ref name="Schaecke" />
== Clinical trials ==
Phase II clinical trials with one of the candidate compounds, mapracorat (code names BOL-303242-X and ZK&nbsp;245186<ref name="Cavet" />), 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]].<ref name="NCT00944632" /> A Phase III trial started in November 2010, evaluating an [[Ophthalmology|ophthalmic]] [[Suspension (chemistry)|suspension]] for the treatment of inflammation following cataract surgery, conducted by [[Bausch & Lomb]].<ref name="NCT01230125" />
A phase II trial with another dissociated glucocorticoid [[fosdagrocorat]] (PF-04171327) (a phosphate ester [[prodrug]] of [[dagrocorat]] (PF-00251802)<ref name="urlAmerican College of Rheumatology"/><ref name="pmid21558312"/>) for rheumatoid arthritis was started in 2011 by [[Pfizer]].<ref name="NCT01393639"/>
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.<ref name="Schaecke2002"/> 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.<ref name="Kerscher"/> 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 [[TSC22D3|GILZ]] and [[DUSP1]], do seem to play an important role.<ref name="Newton 2014"/><ref name="Ayroldi 2014"/> Nevertheless, the more selective nature of these SEGRAMs would still reduce the number of GR-mediated side effects, and deserves further clinical testing.
== Chemistry ==
[[File:RU 24858 skeletal.svg|class=skin-invert-image|thumb|RU 24858, a SEGRA with steroid structure<ref name="Vayssiere" />]]
[[File:Octahydrophenanthrene-2,7-diol SEGRA.svg|class=skin-invert-image|thumb|An octahydrophenanthrene-2,7-diol derivative with SEGRA properties<ref name="Robinson" />]]
Early SEGRAs were synthetic steroids. An example is RU&nbsp;24858, one of the first compounds of this type to be published.<ref name="Vayssiere" /> Many newer SEGRAs have a different framework, although the similarity to steroids can still be seen in molecules like the benzopyranoquinoline A&nbsp;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.<ref name="Robinson" />
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&nbsp;216348<ref name="ZK 209614" /> and 55D1E1.<ref name="Biggadike" /> The bulky, bicyclic aromatic substituents (R<sup>1</sup> and R<sup>2</sup>) account for the structural similarity to corticoids. The [[Cahn–Ingold–Prelog priority rules|''R'' conformation]] of the [[asymmetric carbon]] atom seems to be essential for GR affinity.<ref name="ZK 209614" />
[[File:Trifluoroisopropanolamine SEGRA.svg|class=skin-invert-image|450px]]
==List of SEGRMs==
* [[Dagrocorat]] (PF-00251802, PF-251802)
* [[Fosdagrocorat]] (PF-04171327, PF-4171327)
* [[Mapracorat]] (BOL-303242-X, ZK-245186)
== See also ==
{{Commons category|Selective glucocorticoid receptor agonists}}
* [[Selective receptor modulator]]
* [[Selective androgen receptor modulator]]
* [[Selective estrogen receptor modulator]]
* [[Selective progesterone receptor modulator]]
== References ==
{{Reflist|35em|refs=
<ref name="Sundahl P&T 2015">{{cite journal | vauthors = Sundahl N, Bridelance J, Libert C, De Bosscher K, Beck IM | title = Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds | journal = Pharmacology & Therapeutics | volume = 152| date = May 2015 | pmid = 25958032 | doi = 10.1016/j.pharmthera.2015.05.001 | pages=28–41| doi-access = free | hdl = 1854/LU-6896362 | hdl-access = free }}</ref>
<ref name="Yemelyanov 2008">{{cite journal | vauthors = Yemelyanov A, Czwornog J, Gera L, Joshi S, Chatterton RT, Budunova I | title = Novel steroid receptor phyto-modulator compound a inhibits growth and survival of prostate cancer cells | journal = Cancer Research | volume = 68 | issue = 12 | pages = 4763–73 | date = Jun 2008 | pmid = 18559523 | doi = 10.1158/0008-5472.CAN-07-6104 | url = http://cancerres.aacrjournals.org/content/68/12/4763.long }}</ref>
<ref name="Lesovaya 2011">{{cite journal | vauthors = Lesovaya EA, Yemelyanov AY, Kirsanov KI, Yakubovskaya MG, Budunova IV | title = Antitumor effect of non-steroid glucocorticoid receptor ligand CpdA on leukemia cell lines CEM and K562 | journal = Biochemistry. Biokhimiia | volume = 76 | issue = 11 | pages = 1242–52 | date = Nov 2011 | pmid = 22117551 | doi = 10.1134/S000629791111006X | s2cid = 35234449 | url = http://download-v2.springer.com/static/pdf/110/art%253A10.1134%252FS000629791111006X.pdf?token2=exp=1432824432~acl=%2Fstatic%2Fpdf%2F110%2Fart%25253A10.1134%25252FS000629791111006X.pdf*~hmac=20c26e0aa2b44597b9a9085299d9305992a1fff3a399e33684d79db31aca4732 | access-date = 2015-05-28 | archive-date = 2016-03-11 | archive-url = https://web.archive.org/web/20160311080846/http://download-redirector.springer.com/content/static/pdf/110/art%3A10.1134%2FS000629791111006X.pdf?token2=exp=1432824432~acl=/static/pdf/110/art%253A10.1134%252FS000629791111006X.pdf*~hmac=20c26e0aa2b44597b9a9085299d9305992a1fff3a399e33684d79db31aca4732 | url-status = dead }}</ref>
<ref name="Prous">{{cite journal | title=36th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF) |author1=Mealy N |author2=Dulsat C | journal = Drugs Fut| year = 2009 | volume = 34 | issue = 4 | page = 341 }}</ref>
<ref name="Robinson">{{cite journal | vauthors = Robinson RP, Buckbinder L, Haugeto AI, McNiff PA, Millham ML, Reese MR, Schaefer JF, Abramov YA, Bordner J, Chantigny YA, Kleinman EF, Laird ER, Morgan BP, Murray JC, Salter ED, Wessel MD, Yocum SA | title = Octahydrophenanthrene-2,7-diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 6 | pages = 1731–43 | date = Mar 2009 | pmid = 19239259 | doi = 10.1021/jm801512v }}</ref>
<ref name="Biggadike">{{cite journal | vauthors = Biggadike K, Boudjelal M, Clackers M, Coe DM, Demaine DA, Hardy GW, Humphreys D, Inglis GG, Johnston MJ, Jones HT, House D, Loiseau R, Needham D, Skone PA, Uings I, Veitch G, Weingarten GG, McLay IM, Macdonald SJ | title = Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 26 | pages = 6519–34 | date = Dec 2007 | pmid = 18038970 | doi = 10.1021/jm070778w }}</ref>
<ref name="NCT00944632">{{ClinicalTrialsGov|NCT00944632|Dose Escalation of Different Concentrations of ZK 245186 in Atopic Dermatitis}}</ref>
<ref name="NCT01230125">{{ClinicalTrialsGov|NCT01230125|Mapracorat Ophthalmic Suspension for the Treatment of Ocular Inflammation Following Cataract Surgery}}</ref>
<ref name="NCT01393639">{{ClinicalTrialsGov|NCT01393639|Study Comparing Doses Of An Experimental Glucocorticoid Compound To Prednisone And Placebo In Rheumatoid Arthritis}}</ref>
<!-- <ref name="Zhang">{{vcite2 journal | vauthors = Zhang JZ, Cavet ME, VanderMeid KR, Salvador-Silva M, López FJ, Ward KW | title = BOL-303242-X, a novel selective glucocorticoid receptor agonist, with full anti-inflammatory properties in human ocular cells | journal = Mol. Vis. | volume = 15 | issue = | pages = 2606–16 | year = 2009 | pmid = 20011631 | pmc = 2790480 | doi = }}</ref>-->
<ref name="OEAZ">{{cite journal | vauthors = Heinemann A, Schuligoi R | journal = Österreichische Apothekerzeitung | year = 2008 | volume = 62 | issue = 23 | title = Glucocorticoide – potent und umstritten | trans-title = Glucocorticoids – potent and controversial | url = http://www.oeaz.at/zeitung/3aktuell/2008/23/haupt/haupt23_2008_gluco.html | language = de }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
<ref name="Schaecke">{{cite journal | vauthors = Schäcke H, Berger M, Rehwinkel H, Asadullah K | title = Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index | journal = Molecular and Cellular Endocrinology | volume = 275 | issue = 1–2 | pages = 109–17 | date = Sep 2007 | pmid = 17630119 | doi = 10.1016/j.mce.2007.05.014 | s2cid = 46020217 | url = https://hal.archives-ouvertes.fr/hal-00531931/file/PEER_stage2_10.1016%252Fj.mce.2007.05.014.pdf }}</ref>
<ref name="Schaecke2002">{{cite conference | vauthors = Schäcke H, Hennekes H, Schottelius A, Jaroch S, Lehmann M, Schmees N, Rehwinkel H, Asadullah K | chapter = SEGRAs: A Novel Class of Anti-inflammatory Compounds | series = Ernst Schering Research Foundation Workshop | title = Recent Advances in Glucocorticoid Receptor Action | volume = 40 | pages = 357–71 | year = 2002 | pmid = 12355726 | doi =  10.1007/978-3-662-04660-9_20| isbn = 978-3-662-04662-3 | publisher =Springer | veditors= Cato AC, Schäcke H, Asadullah K }}</ref>
<ref name="A 276575">{{cite journal | vauthors = Lin CW, Nakane M, Stashko M, Falls D, Kuk J, Miller L, Huang R, Tyree C, Miner JN, Rosen J, Kym PR, Coghlan MJ, Carter G, Lane BC | title = trans-Activation and repression properties of the novel nonsteroid glucocorticoid receptor ligand 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four stereoisomers | journal = Molecular Pharmacology | volume = 62 | issue = 2 | pages = 297–303 | date = Aug 2002 | pmid = 12130681 | doi = 10.1124/mol.62.2.297 }}</ref>
<ref name="ZK 209614">{{cite journal | vauthors = Schäcke H, Schottelius A, Döcke WD, Strehlke P, Jaroch S, Schmees N, Rehwinkel H, Hennekes H, Asadullah K | title = Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 227–32 | date = Jan 2004 | pmid = 14694204 | pmc = 314167 | doi = 10.1073/pnas.0300372101 | bibcode = 2004PNAS..101..227S | doi-access = free }}</ref>
<ref name="Newton 2014">{{cite journal | vauthors = Shah S, King EM, Chandrasekhar A, Newton R | title = Roles for the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, in feedback control of inflammatory gene expression and repression by dexamethasone | journal = The Journal of Biological Chemistry | volume = 289 | issue = 19 | pages = 13667–79 | date = May 2014 | pmid = 24692548 | doi = 10.1074/jbc.M113.540799 | pmc=4036371| doi-access = free }}</ref>
<ref name="Ayroldi 2014">{{cite journal | vauthors = Ayroldi E, Macchiarulo A, Riccardi C | title = Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid-induced leucine zipper? A perspective | journal = FASEB Journal | volume = 28 | issue = 12 | pages = 5055–70 | date = December 2014 | pmid = 25205742 | doi = 10.1096/fj.14-254755 | doi-access = free | s2cid = 40874311 }}</ref>
<ref name="Vayssiere">{{cite journal | vauthors = Vayssière BM, Dupont S, Choquart A, Petit F, Garcia T, Marchandeau C, Gronemeyer H, Resche-Rigon M | title = Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo | journal = Molecular Endocrinology | volume = 11 | issue = 9 | pages = 1245–55 | date = Aug 1997 | pmid = 9259316 | doi = 10.1210/mend.11.9.9979 | s2cid = 28436574 | doi-access = free }}</ref>
<ref name="Coghlan">{{cite journal | vauthors = Coghlan MJ, Jacobson PB, Lane B, Nakane M, Lin CW, Elmore SW, Kym PR, Luly JR, Carter GW, Turner R, Tyree CM, Hu J, Elgort M, Rosen J, Miner JN | title = A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects | journal = Molecular Endocrinology | volume = 17 | issue = 5 | pages = 860–9 | date = May 2003 | pmid = 12586843 | doi = 10.1210/me.2002-0355 | s2cid = 10888190 }}</ref>
<ref name="Kerscher">{{cite journal | vauthors = Kerscher MJ, Hart H, Korting HC, Stalleicken D | title = In vivo assessment of the atrophogenic potency of mometasone furoate, a newly developed chlorinated potent topical glucocorticoid as compared to other topical glucocorticoids old and new | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 33 | issue = 4 | pages = 187–9 | date = Apr 1995 | pmid = 7620686 }}</ref>
<ref name="pmid16236742">{{cite journal | vauthors = Rhen T, Cidlowski JA | title = Antiinflammatory action of glucocorticoids--new mechanisms for old drugs | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1711–23 | date = Oct 2005 | pmid = 16236742 | doi = 10.1056/NEJMra050541 | s2cid = 5744727 }}</ref>
<ref name="pmid17622575">{{cite journal | vauthors = Newton R, Holden NS | title = Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? | journal = Molecular Pharmacology | volume = 72 | issue = 4 | pages = 799–809 | date = Oct 2007 | pmid = 17622575 | doi = 10.1124/mol.107.038794 | s2cid = 52803631 }}</ref>
<ref name="pmid9604929">{{cite journal | vauthors = Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, Schütz G | title = DNA binding of the glucocorticoid receptor is not essential for survival | journal = Cell | volume = 93 | issue = 4 | pages = 531–41 | date = May 1998 | pmid = 9604929 | doi = 10.1016/S0092-8674(00)81183-6 | s2cid = 6524157 | doi-access = free }}</ref>
<ref name="pmid11076028">{{cite journal | vauthors = Reichardt HM, Tronche F, Bauer A, Schütz G | title = Molecular genetic analysis of glucocorticoid signaling using the Cre/loxP system | journal = Biological Chemistry | volume = 381 | issue = 9–10 | pages = 961–4 | year = 2000 | pmid = 11076028 | doi = 10.1515/BC.2000.118 | doi-broken-date = 3 December 2024 | s2cid = 37837380 }}</ref>
<ref name="Cavet">{{cite journal | vauthors = Cavet ME, Harrington KL, Ward KW, Zhang JZ | title = Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells | journal = Molecular Vision | volume = 16 | pages = 1791–800 | year = 2010 | pmid = 20824100 | pmc = 2932489 }}</ref>
<ref name="urlAmerican College of Rheumatology">{{cite journal | url = http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=761&id=80053 | title = Evaluation Of Safety, Pharmacokinetics And Pharmacodynamics Of A Selective Glucocorticoid Receptor Modulator (SGRM) In Healthy Volunteers | vauthors = Stock T, Fleishaker D, Mukherjee A, Le V, Xu J, Zeiher B | journal =  Arthritis Rheum |year=2009 |volume=60 |issue=Suppl 10 |page=420 | doi = 10.1002/art.25503 | doi-broken-date = 1 November 2024 |archive-url=https://web.archive.org/web/20160303222256/http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=761&id=80053| archive-date = 2016-03-03 |url-status=dead}}</ref>
<ref name="pmid21558312">{{cite journal | vauthors = Hu X, Du S, Tunca C, Braden T, Long KR, Lee J, Webb EG, Dietz JD, Hummert S, Rouw S, Hegde SG, Webber RK, Obukowicz MG | title = The antagonists but not partial agonists of glucocorticoid receptor ligands show substantial side effect dissociation | journal = Endocrinology | volume = 152 | issue = 8 | pages = 3123–34 | date = Aug 2011 | pmid = 21558312 | doi = 10.1210/en.2010-1447 | doi-access = free }}</ref>
}}
==Further reading==
*{{cite book |last1=Hobson |first1=Adrian |title=The Medicinal Chemistry of Glucocorticoid Receptor Modulators |date=2023 |publisher=Springer Nature |isbn=978-3-031-28732-9 |language=en}}
{{Glucocorticoids and antiglucocorticoids}}
{{Glucocorticoid receptor modulators}}
[[Category:Anti-inflammatory agents]]
[[Category:Immunosuppressants]]
[[Category:Selective glucocorticoid receptor modulators]]