title: Design and synthesis of novel p38α MAP kinase inhibitors: discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety.
abstract: The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.
authors: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan. Tadamasa_Arai@nts.toray.co.jp
authors: Tadamasa
authors: T
authors: Arai
authors: Michihiro
authors: M
authors: Ohno
authors: Hideki
authors: H
authors: Inoue
authors: Shinnosuke
authors: S
authors: Hayashi
authors: Takumi
authors: T
authors: Aoki
authors: Hiroe
authors: H
authors: Hirokawa
authors: Hiroyuki
authors: H
authors: Meguro
authors: Yoko
authors: Y
authors: Koga
authors: Keiyu
authors: K
authors: Oshida
authors: Mie
authors: M
authors: Kainoh
authors: Kazuharu
authors: K
authors: Suyama
authors: Hideki
authors: H
authors: Kawai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D010671:Phenylurea Compounds
chemical_list: D003577:Cytochrome P-450 Enzyme System; D007093:Imidazoles; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; C031280:pyrazole; C452139:doramapimod; D010671:Phenylurea Compounds; C030986:pyrimidine; C093642:SB 203580