ORG-224283

ORG-224283 is a small molecule selective glucocorticoid receptor agonist (SGRM), also referred to as a dissociated glucocorticoid, originally developed by Organon (later acquired by Schering-Plough and subsequently Merck & Co.). It was engineered to provide the potent anti-inflammatory and immunosuppressive benefits of traditional corticosteroids while minimizing the systemic side effects associated with long-term steroid use, such as osteoporosis, skin thinning, and glucose intolerance. The compound's mechanism focuses on favoring transrepression—the inhibition of pro-inflammatory transcription factors like NF-κB and AP-1—over transactivation, which is the process responsible for many metabolic side effects. ORG-224283 reached Phase 2 clinical development for the treatment of rheumatoid arthritis, but development was ultimately discontinued.