LGD-5552, an antiinflammatory glucocorticoid receptor ligand with reduced side effects, in vivo.
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.
López
Francisco J
FJ
Discovery Research, Ligand Pharmaceuticals, San Diego, California 92121, USA.
Ardecky
Robert J
RJ
Bebo
Bruce
B
Benbatoul
Khalid
K
De Grandpre
Louise
L
Liu
Sha
S
Leibowitz
Mark D
MD
Marschke
Keith
K
Rosen
Jon
J
Rungta
Deepa
D
Viveros
Humberto O
HO
Yen
Wan-Ching
WC
Zhi
Lin
L
Negro-Vilar
Andrés
A
Miner
Jeffrey N
JN
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
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