title: LGD-5552, an antiinflammatory glucocorticoid receptor ligand with reduced side effects, in vivo.
abstract: Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.
authors.affiliation: Discovery Research, Ligand Pharmaceuticals, San Diego, California 92121, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Bruce
authors.initials: B
authors.lastname: Bebo
authors.forename: Khalid
authors.initials: K
authors.lastname: Benbatoul
authors.forename: Louise
authors.initials: L
authors.lastname: De Grandpre
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Mark D
authors.initials: MD
authors.lastname: Leibowitz
authors.forename: Keith
authors.initials: K
authors.lastname: Marschke
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: Deepa
authors.initials: D
authors.lastname: Rungta
authors.forename: Humberto O
authors.initials: HO
authors.lastname: Viveros
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Yen
authors.forename: Lin
authors.initials: L
authors.lastname: Zhi
authors.forename: Andrés
authors.initials: A
authors.lastname: Negro-Vilar
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001578:Benzopyrans / Q000009:adverse effects* / Q000627:therapeutic use*; D001597:Benzylidene Compounds / Q000009:adverse effects* / Q000627:therapeutic use*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D008297:Male; D008954:Models, Biological; D011239:Prednisolone / Q000009:adverse effects / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D018411:Spodoptera; D013379:Substrate Specificity
chemical_list: C525875:5-((2-fluoro-3-methylphenyl)methylene)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinolin-9-ol; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D001597:Benzylidene Compounds; D008024:Ligands; D011965:Receptors, Glucocorticoid; D011239:Prednisolone