Periodic, Partial Inhibition Of I Kappa B Kinase Beta-Mediated Signaling Yields Therapeutic Benefit In Preclinical Models Of Rheumatoid Arthritis

We have previously shown that inhibitors of I kappa B kinase beta(IKK beta), 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 IKK beta 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 IKK beta 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 IKK beta by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to auto-immunity 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 IKK beta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKK beta inhibitors.