FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice.
Extracellular signal-regulated kinase (ERK), a serine/threonine protein kinase of the mitogen-activated protein kinase superfamily, is activated by various stimuli in inflammatory cells. We recently described FR180204 (5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-amine), a novel selective ERK inhibitor. In this paper, we investigated the effect of FR180204 on collagen-induced arthritis (CIA) in DBA/1 mice, an animal model of rheumatoid arthritis (RA) mediated by type II collagen (CII)-reactive T cells and anti-CII antibodies. Preventive administration of FR180204 (100 mg/kg, i.p., b.i.d.) significantly ameliorated the clinical arthritis and body weight loss occurring in the CIA mice. Further, FR180204-treated mice showed a significant decrease in plasma anti-CII antibody levels (62%). FR180204 also attenuated delayed-type hypersensitivity in CII-immunized DBA/1 mice, an inflammatory response elicited by CII-reactive T cells, in a dose-dependent manner (52 and 62% inhibition at 32 and 100 mg/kg, respectively). Moreover, FR180204 inhibited in vitro CII-induced proliferation of lymph node cells prepared from CII-immunized mice, in which CII-specific T cells are known to undergo specific proliferation. In conclusion, our results suggest that ERK regulates both the cell-mediated and humoral immune responses in the development of CIA. ERK inhibitors may be useful as therapeutic reagents for the treatment of RA.
Ohori
Makoto
M
Lead Discovery Research Labs, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki, Japan. makoto.ohoi@jp.astellas.com
Takeuchi
Mikio
M
Maruki
Riyo
R
Nakajima
Hidenori
H
Miyake
Hiroshi
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D024043:Collagen Type II / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007132:Immunoglobulin Isotypes / Q000097:blood; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013936:Thymidine / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D024043:Collagen Type II; C505241:FR 180204; D005938:Glucocorticoids; D007132:Immunoglobulin Isotypes; D011720:Pyrazoles; D011724:Pyridazines; D048049:Extracellular Signal-Regulated MAP Kinases; D013936:Thymidine; D008775:Methylprednisolone