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: Kathleen M Gillooly, Mark A Pattoli, Tracy L Taylor, Laishun Chen, Lihong Cheng, Kurt R Gregor, Gena S Whitney, Vojkan Susulic, Scott H Watterson, James Kempson, William J Pitts, Hollie Booth-Lute, Guchen Yang, Paul Davies, Daniel W Kukral, Joann Strnad, Kim W McIntyre, Celia J Darienzo, Luisa Salter-Cid, Zheng Yang, David B Wang-Iverson, James R Burke
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 331 Issue 2 Pg. 349-60 (Nov 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19652024 (Publication Type: Journal Article)

Chemical References

• 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
• Acetamides
• Heterocyclic Compounds, 3-Ring
• I-kappa B Proteins
• Immunoglobulins
• Lipopolysaccharides
• Protein Kinase Inhibitors
• Tumor Necrosis Factor-alpha
• Collagen
• I-kappa B Kinase

Topics

• Acetamides (pharmacokinetics, pharmacology, therapeutic use)
• Animals
• Arthritis, Experimental (chemically induced, drug therapy, pathology)
• Arthritis, Rheumatoid (chemically induced, drug therapy, pathology)
• Autoimmunity (drug effects)
• Cell Proliferation (drug effects)
• Collagen
• Heterocyclic Compounds, 3-Ring (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• I-kappa B Kinase (antagonists & inhibitors)
• I-kappa B Proteins (metabolism)
• Immunoglobulins (biosynthesis)
• In Vitro Techniques
• Joints (pathology)
• Jurkat Cells
• Lipopolysaccharides
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Monocytes (drug effects)
• Osteoclasts (drug effects)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Inbred Lew
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (biosynthesis)