Novel p38 inhibitors with potent oral efficacy in several 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 p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
Revesz
Laszlo
L
Novartis Institutes for BioMedical Research, Arthritis & Bone Metabolism, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com
Blum
Ernst
E
Di Padova
Franco E
FE
Buhl
Thomas
T
Feifel
Roland
R
Gram
Hermann
H
Hiestand
Peter
P
Manning
Ute
U
Rucklin
Gerard
G
D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D003094:Collagen; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010080:Oxazoles / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D010080:Oxazoles; D011725:Pyridines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases