1. A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects.
- Author
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Coghlan MJ, Jacobson PB, Lane B, Nakane M, Lin CW, Elmore SW, Kym PR, Luly JR, Carter GW, Turner R, Tyree CM, Hu J, Elgort M, Rosen J, and Miner JN
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Anti-Inflammatory Agents, Non-Steroidal metabolism, Arthritis, Experimental drug therapy, Benzopyrans adverse effects, Benzopyrans metabolism, Bone and Bones drug effects, Cells, Cultured, Drug Evaluation, Preclinical methods, Edema drug therapy, Gene Expression Regulation drug effects, Glucocorticoids pharmacology, Humans, Inflammation drug therapy, Male, Nuclear Receptor Coactivator 2, Prednisolone metabolism, Prednisolone pharmacology, Quinolines adverse effects, Quinolines metabolism, Rats, Rats, Sprague-Dawley, Tibia anatomy & histology, Tibia drug effects, Transcription Factors drug effects, Transcription Factors genetics, Transcription Factors metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Benzopyrans pharmacology, Quinolines pharmacology
- Abstract
Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor gamma coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.
- Published
- 2003
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