Abstract
We have previously shown that inhibitors of IκB kinase β (IKKβ), 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 IKKβ 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 α 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 IKKβ 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 IKKβ 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, TH17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKKβ is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKβ inhibitors.
- IKK, IκB kinase
- BCR, B cell receptor
- KLH, keyhole limpet hemocyanin
- LPS, lipopolysaccharide
- PBMC, peripheral blood mononuclear cell
- TCR, T cell receptor
- NF-κB, nuclear factor κB
- TNF-α, tumor necrosis factor α
- DMSO, dimethyl sulfoxide
- ELISA, enzyme-linked immunosorbent assay
- LC/MS/MS, liquid chromatography coupled to tandem mass spectrometry
- PEG400, Polyethylene Glycol 400
- Pen/Strep, penicillin and streptomycin mixture
- RANKL, receptor activator of NF-κB ligand
- NFAT, nuclear factor of activated T cells
- TRAP, tartrate-resistant acid phosphatase
- IL, interleukin
- FBS, fetal bovine serum
- micro-CT, microcomputed tomography
- BMS-345541, 4(2′-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
- BMS-066, 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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.156018
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- Received May 7, 2009.
- Accepted July 31, 2009.
- © 2009 by the American Society for Pharmacology and Experimental Therapeutics
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