Periodic, partial inhibition of IkappaB Kinase beta-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritis.
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.
Gillooly
Kathleen M
KM
Departments of Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
Pattoli
Mark A
MA
Taylor
Tracy L
TL
Chen
Laishun
L
Cheng
Lihong
L
Gregor
Kurt R
KR
Whitney
Gena S
GS
Susulic
Vojkan
V
Watterson
Scott H
SH
Kempson
James
J
Pitts
William J
WJ
Booth-Lute
Hollie
H
Yang
Guchen
G
Davies
Paul
P
Kukral
Daniel W
DW
Strnad
Joann
J
McIntyre
Kim W
KW
Darienzo
Celia J
CJ
Salter-Cid
Luisa
L
Yang
Zheng
Z
Wang-Iverson
David B
DB
Burke
James R
JR
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
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