title: The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator.
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.
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States. Electronic address: philip.brandish@merck.com.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Baltus
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Chang
authors.initials: C
authors.lastname: Bai
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bungard
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bunting
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Byford
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Chi-Sung
authors.initials: CS
authors.lastname: Chiu
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Milenko
authors.initials: M
authors.lastname: Cicmil
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Halea
authors.initials: H
authors.lastname: Corcoran
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Euler
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Fisher
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambone
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Martha
authors.initials: M
authors.lastname: Hasbun-Manning
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Nelly
authors.initials: N
authors.lastname: Kuklin
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Landis
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Traci Q
authors.initials: TQ
authors.lastname: Lifsted
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Sheila
authors.initials: S
authors.lastname: McElwee-Witmer
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Ian S
authors.initials: IS
authors.lastname: McIntosh
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: John
authors.initials: J
authors.lastname: Miao
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mitchell
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Musselman
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Azriel
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: John
authors.initials: J
authors.lastname: Shin
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Szczerba
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.affiliation: Merck & Co., Inc., Boston, MA 02115, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tribouley
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vogel
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: Sudha
authors.initials: S
authors.lastname: Warrier
authors.affiliation: Merck & Co., Inc., West Point, PA 19422, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Hershey
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003094:Collagen; D016207:Cytokines / Q000097:blood; D003877:Dermatitis, Contact / Q000188:drug therapy*; D004285:Dogs; D004487:Edema / Q000188:drug therapy*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin; D008070:Lipopolysaccharides; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: C000592348:5-fluoro-2-(2-(1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta(f)indazol-5-yl)ethyl)benzamide; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D016207:Cytokines; D007191:Indazoles; D007328:Insulin; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D003094:Collagen; D008775:Methylprednisolone
keywords: Diabetes; Glucocorticoid; Glucocorticoid receptor; Glucose; MK-5932