title: Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index.
abstract: Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.
authors.affiliation: Department of Immune Therapeutics, MSD, Oss, The Netherlands. mariejose.vanlierop@merck.com
authors.forename: Marie-José C
authors.initials: MJ
authors.lastname: van Lierop
authors.forename: Wynand
authors.initials: W
authors.lastname: Alkema
authors.forename: Anke J
authors.initials: AJ
authors.lastname: Laskewitz
authors.forename: Rein
authors.initials: R
authors.lastname: Dijkema
authors.forename: Hans M
authors.initials: HM
authors.lastname: van der Maaden
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Ralf
authors.initials: R
authors.lastname: Plate
authors.forename: Paolo G M
authors.initials: PG
authors.lastname: Conti
authors.forename: Christan G J M
authors.initials: CG
authors.lastname: Jans
authors.forename: C Marco
authors.initials: CM
authors.lastname: Timmers
authors.forename: Constant A A
authors.initials: CA
authors.lastname: van Boeckel
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Lusher
authors.forename: Ross
authors.initials: R
authors.lastname: McGuire
authors.forename: Rene C
authors.initials: RC
authors.lastname: van Schaik
authors.forename: Jacob
authors.initials: J
authors.lastname: de Vlieg
authors.forename: Ruben L
authors.initials: RL
authors.lastname: Smeets
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Hofstra
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
authors.forename: Marcel
authors.initials: M
authors.lastname: van Duin
authors.forename: Benno A
authors.initials: BA
authors.lastname: Ingelse
authors.forename: Willem G E J
authors.initials: WG
authors.lastname: Schoonen
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Wim H A
authors.initials: WH
authors.lastname: Dokter
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000235:genetics; D001786:Blood Glucose; D003984:Dibenzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D003984:Dibenzazepines; C580745:N-(8-cyano-1,2,3,4,10,14b-hexahydro-10-methyl dibenzo(c,f)pyrido(1,2-a)azepin-2-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide; D011965:Receptors, Glucocorticoid; D013830:Thiadiazoles; D011239:Prednisolone