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

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

Research output: Contribution to journalArticle

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Abstract

Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.

Original languageEnglish
Pages (from-to)102-111
Number of pages10
JournalEuropean Journal of Pharmacology
Volume724
Issue number1
DOIs
Publication statusPublished - 05-02-2014
Externally publishedYes

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Glucocorticoid Receptors
Insulin
Glucose
Experimental Arthritis
Anti-Inflammatory Agents
Oral Administration
Lipopolysaccharides
Cytokines
5-fluoro-2-(2-(1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta(f)indazol-5-yl)ethyl)benzamide
Contact Dermatitis
Methylprednisolone
Prednisone
Glucocorticoids
Fasting
Neutrophils
Therapeutics
Dogs
Ligands
Serum
Genes

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Brandish, Philip E. ; Anderson, Kenneth ; Baltus, Gretchen A. ; Bai, Chang ; Bungard, Christopher J. ; Bunting, Patricia ; Byford, Alan ; Chiu, Chi Sung ; Cicmil, Milenko ; Corcoran, Halea ; Euler, Danielle ; Fisher, John E. ; Gambone, Carlo ; Hasbun-Manning, Martha ; Kuklin, Nelly ; Landis, Elizabeth ; Lifsted, Traci Q. ; McElwee-Witmer, Sheila ; McIntosh, Ian S. ; Meissner, Robert S. ; 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. / The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator. In: European Journal of Pharmacology. 2014 ; Vol. 724, No. 1. pp. 102-111.
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Brandish, PE, Anderson, K, Baltus, GA, Bai, C, Bungard, CJ, Bunting, P, Byford, A, Chiu, CS, Cicmil, M, Corcoran, H, Euler, D, Fisher, JE, Gambone, C, Hasbun-Manning, M, Kuklin, N, Landis, E, Lifsted, TQ, McElwee-Witmer, S, McIntosh, IS, Meissner, RS, Miao, J, Mitchell, HJ, Musselman, A, Schmidt, A, Shin, J, Szczerba, P, Thompson, CD, Tribouley, C, Vogel, RL, Warrier, S & Hershey, JC 2014, 'The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator', European Journal of Pharmacology, vol. 724, no. 1, pp. 102-111. https://doi.org/10.1016/j.ejphar.2013.12.031

The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator. / Brandish, Philip E.; Anderson, Kenneth; Baltus, Gretchen A.; Bai, Chang; Bungard, Christopher J.; Bunting, Patricia; Byford, Alan; Chiu, Chi Sung; Cicmil, Milenko; Corcoran, Halea; Euler, Danielle; Fisher, John E.; Gambone, Carlo; Hasbun-Manning, Martha; Kuklin, Nelly; Landis, Elizabeth; Lifsted, Traci Q.; McElwee-Witmer, Sheila; McIntosh, Ian S.; Meissner, Robert S.; 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.

In: European Journal of Pharmacology, Vol. 724, No. 1, 05.02.2014, p. 102-111.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator

AU - Brandish, Philip E.

AU - Anderson, Kenneth

AU - Baltus, Gretchen A.

AU - Bai, Chang

AU - Bungard, Christopher J.

AU - Bunting, Patricia

AU - Byford, Alan

AU - Chiu, Chi Sung

AU - Cicmil, Milenko

AU - Corcoran, Halea

AU - Euler, Danielle

AU - Fisher, John E.

AU - Gambone, Carlo

AU - Hasbun-Manning, Martha

AU - Kuklin, Nelly

AU - Landis, Elizabeth

AU - Lifsted, Traci Q.

AU - McElwee-Witmer, Sheila

AU - McIntosh, Ian S.

AU - Meissner, Robert S.

AU - Miao, John

AU - Mitchell, Helen J.

AU - Musselman, Amy

AU - Schmidt, Azriel

AU - Shin, John

AU - Szczerba, Peter

AU - Thompson, Charles D.

AU - Tribouley, Catherine

AU - Vogel, Robert L.

AU - Warrier, Sudha

AU - Hershey, James C.

PY - 2014/2/5

Y1 - 2014/2/5

N2 - Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.

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