Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 13; pp. 3595 - 3599
• Main Authors: Revesz, Laszlo, Blum, Ernst, Di Padova, Franco E., Buhl, Thomas, Feifel, Roland, Gram, Hermann, Hiestand, Peter, Manning, Ute, Rucklin, Gerard
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.07.2004; Elsevier
• Subjects: Animals; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Collagen; Disease Models, Animal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Imidazoles - chemistry; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Oxazoles - chemistry; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Structure-Activity Relationship; Thiazoles - chemistry; Tumor Necrosis Factor-alpha - metabolism; Imidazole derivatives; Rat; Nitrogen heterocycle; Thiazole derivatives; Diseases of the osteoarticular system; Autoimmune disease; Arthritis; Inflammatory joint disease; Pyridine derivatives; Signal transduction; Structure activity relation; Chemical compound library; Adjuvant; Inhibition; Chemical synthesis; Tumor necrosis factor α; Release; Oxygen nitrogen heterocycle; Immunopathology; Sulfur nitrogen heterocycle; Enzyme; Transferases; Rodentia; Antiinflammatory agent; Cytokine; Oral administration; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Protein kinase; Animal; Rheumatoid arthritis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.03.106

A pilot library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2- b]pyridines was prepared and evaluated in vitro and in vivo as p38α inhibitors. Four structures–– 32, 37, 45 and 59––were identified as potent inhibitors of p38α with high oral efficacy in three models of rheumatoid arthritis. A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2- b]pyridines was prepared and evaluated in vitro as p38α inhibitors and in vivo in several models of rheumatoid arthritis. Four structures–– 32, 37, 45 and 59––were identified as potent inhibitors of p38α with high efficacy in the LPS induced TNFα release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED 50s between 1.0 and 9.5 mg/kg p.o.