Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors.
A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7 g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-alpha). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.
Miwatashi
Seiji
S
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Osaka. Miwatashi_Seiji@takeda.co.jp
Arikawa
Yasuyoshi
Y
Naruo
Ken-Ichi
K
Igaki
Keiko
K
Watanabe
Yasumasa
Y
Kimura
Hiroyuki
H
Kawamoto
Tomohiro
T
Ohkawa
Shigenori
S
D000818:Animals; D000906:Antibodies / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000188:drug therapy; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003094:Collagen / Q000276:immunology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000906:Antibodies; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases