The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator

Brandish, Philip E.; Anderson, Kenneth D.; Baltus, Gretchen A.; Bai, Chang; Bungard, Christopher J.; Bunting, Patricia B.; Byford, Alan; Chiu, Chi Sung; Cicmil, Milenko; Corcoran, Halea A.; Euler, Danielle H.; Fisher, John; Gambone, Carlo J.; Hasbun-Manning, Martha; Kuklin, Nelly A.; Landis, Elizabeth; Lifsted, Traci; McElwee-Witmer, Sheila; McIntosh, Ian; Meißner, Robert; Miao, John; Mitchell, Helen J.; Musselman, Amy; Schmidt, Azriel; Shin, John; Szczerba, Peter; Thompson, Charles D.; Tribouley, Catherine; Vogel, Robert L.; Warrier, Sudha; Hershey, James C.

doi:10.1016/j.ejphar.2013.12.031

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…In vivo studies in rats using AL-438, ZK 216348 or MK-5932 and in mice using Org-214007-0 also supported that these compounds cannot cause an increase in plasma glucose, in contrast to prednisolone (Coghlan et al, 2003;Schacke et al, 2004;Bungard et al, 2011;van Lierop et al, 2012;Brandish et al, 2014). Also contrary to prednisolone therapy, Org-214007-0 did not shift the liver glucose/glycogen balance (van Lierop et al, 2012).…”

Section: Side Effectsmentioning

confidence: 85%

“…With regards to the latter, the anti-inflammatory effects of the test SEGRMs were assessed using inflammatory disease models in vivo, such as allergic conjunctivitis (Baiula et al, 2014), (rheumatoid) arthritis Dewint et al, 2008;López et al, 2008;Thiele et al, 2012;Rauner et al, 2013;Carson et al, 2014), neuro-inflammation (Zhang et al, 2009a;van Loo et al, 2010), asthma (Reber et al, 2012) and colitis (Reuter et al, 2012a,b). Yet, it needs to be said that, although it has been proven that all SEGRMs discussed here (except PF-802) can bind to GR (Coghlan et al, 2003;Schacke et al, 2004Schacke et al, , 2009De Bosscher et al, 2005;Chivers et al, 2006;Miner et al, 2007;Zhang et al, 2009b;van Lierop et al, 2012;Brandish et al, 2014;Carson et al, 2014), only CpdA and ZK 216346 are shown to elicit a partial or full nuclear translocation of GR (De Bosscher et al, 2005;Dewint et al, 2008;Yemelyanov et al, 2008;Robertson et al, 2010;Reuter et al, 2012b;Presman et al, 2014;Drebert et al, 2015) (also see 2.1 Structure of Glucocorticoid receptors). Therefore, it cannot be completely excluded that their observed in vitro and in vivo anti-inflammatory effect is perhaps (partially) mediated by GR-independent action mechanisms.…”

Section: Selective Glucocorticoid Receptor Modulatorsmentioning

confidence: 96%

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Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

186

171

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Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

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Section: Side Effectsmentioning

confidence: 85%

Section: Selective Glucocorticoid Receptor Modulatorsmentioning

confidence: 96%

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

186

171

View full text Add to dashboard Cite

show abstract

“…Selective GR modulators combine GR agonism and antagonism that, upon binding to GR, induce unique receptor conformations that allow interaction with only subsets of downstream signaling pathways. Therapeutic potential has long been recognized for inflammatory disease, but unequivocal in vivo data remain limited, in particular in clinical settings (10)(11)(12). CORT118335 is a selective modulator that induces a profile of GR-coregulator interactions intermediate to full agonists and antagonists (13)(14)(15).…”

Section: A Dmentioning

confidence: 99%

Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice

et al. 2018

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at the modification stage), and do not reflect editorial changes. No corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be differences between the Advance Article manuscripts and the final, typeset articles. The manuscripts remain listed on the Advance Article page until the final, typeset articles are posted. At that point, the manuscripts are removed from the Advance Article page. DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express or particular purpose, or non-infringement. Changes will be made to these manuscripts before publication. Review and/or use or reliance on these materials is at the discretion and risk of the reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising references to, products or publications do not imply endorsement of that product or publication.

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“…The development of new GC therapeutics with distinct activity profiles are showing promise at separating a subset of side effects from the desired anti-inflammatory effects, though their exact mechanisms of achieving this dissociation are still not completely clear (144,145). Several proteins described in this review such as, LXR, FXR, AMPK and HDAC6, are amenable to small molecule targeting and may prove to be effective at limiting GR-mediated side effects when dosed in combination with currently prescribed GCs.…”

Section: Discussionmentioning

confidence: 99%

Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

Patel

Williams-Dautovich

Cummins

2014

Molecular Endocrinology

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The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas.

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The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator

Cited by 11 publications

References 27 publications

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Selective glucocorticoid receptor modulation prevents and reverses non-alcoholic fatty liver disease in male mice

Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

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