title: A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects.
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.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Ben
authors.initials: B
authors.lastname: Lane
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Lin
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Jay R
authors.initials: JR
authors.lastname: Luly
authors.forename: George W
authors.initials: GW
authors.lastname: Carter
authors.forename: Russell
authors.initials: R
authors.lastname: Turner
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Tyree
authors.forename: Junlian
authors.initials: J
authors.lastname: Hu
authors.forename: Marc
authors.initials: M
authors.lastname: Elgort
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001578:Benzopyrans / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004487:Edema / Q000188:drug therapy; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051958:Nuclear Receptor Coactivator 2; D011239:Prednisolone / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000033:anatomy & histology / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: C476829:10-methoxy-5-(2-propenyl)-2,5-dihydro-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinoline; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D005938:Glucocorticoids; D051958:Nuclear Receptor Coactivator 2; D011804:Quinolines; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D011239:Prednisolone