title: Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.
abstract: Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.
authors.affiliation: Discovery Research, Ligand Pharmaceuticals, San Diego, CA 92121, USA. jminer@ligand.com
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
authors.forename: Bob
authors.initials: B
authors.lastname: Ardecky
authors.forename: Khalid
authors.initials: K
authors.lastname: Benbatoul
authors.forename: Kimberly
authors.initials: K
authors.lastname: Griffiths
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Larson
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: Keith
authors.initials: K
authors.lastname: Marschke
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: Eric
authors.initials: E
authors.lastname: Vajda
authors.forename: Lin
authors.initials: L
authors.lastname: Zhi
authors.forename: Andres
authors.initials: A
authors.lastname: Negro-Vilar
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism
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; D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid