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Submitted on October 18, 2002
Accepted on December 23, 2002
1 Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, CA 92121, USA Mayo Clinic, 200 First Street, SW, Rochester MN 55905, USA Present address: Eli Lilly & Co., DC 0528, Lilly Corporate Center, Indianapolis, IN 46285, USA Present address: Millennium Pharmaceuticals, Inc., 75 Sidney St, Cambridge, MA 02139, USA
* To whom correspondence should be addressed. E-mail: jminer{at}ligand.com.
Glucocorticoids 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 anti-inflammatory effects of glucocorticoids are a result of GR-mediated inhibition of expression of pro-inflammatory genes as well as GR mediated activation of anti-inflammatory 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 anti-inflammatory activity. We describe the discovery and characterization of AL-438, a glucocorticoid receptor ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by glucocorticoids. When tested in vivo, AL-438 retains full anti-inflammatory efficacy and potency comparable to steroids, but has less negative effects on bone metabolism and glucose control at equivalently anti-inflammatory 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 glucocorticoid receptor and PGC-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GRIP-1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional glucocorticoids in treating inflammatory disease.
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