title: Periodic, partial inhibition of IkappaB Kinase beta-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritis.
abstract: We have previously shown that inhibitors of IkappaB kinase beta (IKKbeta), including 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKKbeta inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor alpha production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T(H)17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKKbeta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKbeta inhibitors.
authors: Departments of Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors: Kathleen M
authors: KM
authors: Gillooly
authors: Mark A
authors: MA
authors: Pattoli
authors: Tracy L
authors: TL
authors: Taylor
authors: Laishun
authors: L
authors: Chen
authors: Lihong
authors: L
authors: Cheng
authors: Kurt R
authors: KR
authors: Gregor
authors: Gena S
authors: GS
authors: Whitney
authors: Vojkan
authors: V
authors: Susulic
authors: Scott H
authors: SH
authors: Watterson
authors: James
authors: J
authors: Kempson
authors: William J
authors: WJ
authors: Pitts
authors: Hollie
authors: H
authors: Booth-Lute
authors: Guchen
authors: G
authors: Yang
authors: Paul
authors: P
authors: Davies
authors: Daniel W
authors: DW
authors: Kukral
authors: Joann
authors: J
authors: Strnad
authors: Kim W
authors: KW
authors: McIntyre
authors: Celia J
authors: CJ
authors: Darienzo
authors: Luisa
authors: L
authors: Salter-Cid
authors: Zheng
authors: Z
authors: Yang
authors: David B
authors: DB
authors: Wang-Iverson
authors: James R
authors: JR
authors: Burke
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020672:I-kappa B Proteins / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis; D066298:In Vitro Techniques; D007596:Joints / Q000473:pathology; D019169:Jurkat Cells; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C545117:2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimiazo(4,5-d)pyrrolo(2,3-b)pyridin-7-yl)pyridin-2-yl)methyl)acetamide; D000081:Acetamides; D006575:Heterocyclic Compounds, 3-Ring; D020672:I-kappa B Proteins; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D051550:I-kappa B Kinase