title: 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.affiliation: Biological Research Laboratories, Sankyo Co., Ltd. 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. yhwada@sankyo.co.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakajima-Yamada
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamada
authors.forename: Jun
authors.initials: J
authors.lastname: Tsuchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasumoto
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoki
authors.forename: Tomio
authors.initials: T
authors.lastname: Kimura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ushiyama
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D011758:Pyrroles; D048051:p38 Mitogen-Activated Protein Kinases; C497778:2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole