R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models.

Abstract

We found that a novel compound, R-130823 {2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole}, had highly selective inhibition against mitogen-activated protein kinase p38alpha (IC50=22 nM). The release of tumor necrosis factor-alpha, interleukin-1beta, -6 and -8 was inhibited in lipopolysaccharide-stimulated human blood pretreated by R-130823, with IC50 values of 0.089, 0.066, 0.95 and 0.16 microM, respectively. R-130823 reduced the established hind paw swelling in rat adjuvant-induced arthritis, while methotrexate showed no suppression. In the same model, R-130823 ameliorated adjuvant-induced hyperalgesia with rapid onset and long duration comparable to a cyclooxygenase-2 inhibitor, celecoxib. In murine collagen-induced arthritis, R-130823 blocked the progress of arthritis when administered just after the onset of the arthritis. Histological analysis of the knee joints showed that proliferation of fibroblasts and synoviocytes and infiltration of neutrophils were ameliorated. In conclusion, R-130823 is expected to be an efficacious treatment for rheumatoid arthritis by blocking the p38 pathway.

• Authors: Yoshihiro Wada, Tomoko Nakajima-Yamada, Kazuyo Yamada, Jun Tsuchida, Takashi Yasumoto, Takaichi Shimozato, Kazumasa Aoki, Tomio Kimura, Shigeru Ushiyama
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 506 Issue 3 Pg. 285-95 (Jan 04 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15627439 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Enzyme Inhibitors
• Pyridines
• Pyrroles
• p38 Mitogen-Activated Protein Kinases
• 2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole

Topics

• Animals
• Arthritis, Experimental (drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Hyperalgesia (drug therapy, enzymology)
• Male
• Mice
• Mice, Inbred DBA
• Pyridines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Rats
• Rats, Inbred Lew
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)