FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice.

Abstract

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.

• Authors: Makoto Ohori, Mikio Takeuchi, Riyo Maruki, Hidenori Nakajima, Hiroshi Miyake
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 374 Issue 4 Pg. 311-6 (Jan 2007) ISSN: 0028-1298 [Print] Germany
• PMID: 17123065 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Collagen Type II
• FR 180204
• Glucocorticoids
• Immunoglobulin Isotypes
• Pyrazoles
• Pyridazines
• Extracellular Signal-Regulated MAP Kinases
• Thymidine
• Methylprednisolone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Arthritis, Experimental (chemically induced, physiopathology, prevention & control)
• Collagen Type II (antagonists & inhibitors, toxicity)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Glucocorticoids (pharmacology, therapeutic use)
• Hypersensitivity, Delayed (prevention & control)
• Immunoglobulin Isotypes (blood)
• Injections, Intraperitoneal
• Lymphocyte Activation (drug effects)
• Male
• Methylprednisolone (pharmacology, therapeutic use)
• Mice
• Mice, Inbred DBA
• Pyrazoles (administration & dosage, pharmacology, therapeutic use)
• Pyridazines (administration & dosage, pharmacology, therapeutic use)
• T-Lymphocytes (drug effects, immunology)
• Thymidine (metabolism)
• Weight Loss (drug effects)