Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile

Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19244-9. doi: 10.1073/pnas.0705517104. Epub 2007 Nov 21.


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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Rheumatoid / drug therapy*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Benzopyrans / therapeutic use
  • Benzylidene Compounds / chemistry
  • Benzylidene Compounds / pharmacology*
  • Benzylidene Compounds / therapeutic use
  • Cell Line, Tumor
  • Gene Expression / drug effects
  • Glucocorticoids / chemistry
  • Glucocorticoids / pharmacology*
  • Glucocorticoids / therapeutic use
  • Ligands
  • Mice
  • Mice, Inbred Strains
  • Osteogenesis / drug effects
  • Rats
  • Receptors, Glucocorticoid / antagonists & inhibitors*
  • Receptors, Glucocorticoid / metabolism


  • 5-((2-fluoro-3-methylphenyl)methylene)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinolin-9-ol
  • Anti-Inflammatory Agents
  • Benzopyrans
  • Benzylidene Compounds
  • Glucocorticoids
  • Ligands
  • Receptors, Glucocorticoid