SAR of 2,6-diamino-3,5-difluoropyridinyl substituted heterocycles as novel p38MAP kinase inhibitors.
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.
Arthritis and Bone Research, Novartis Pharma AG, CH-4002, Basel, Switzerland. laszlo.revesz@pharma.novartis.com
Laszlo
L
Revesz
Franco E
FE
Di Padova
Thomas
T
Buhl
Roland
R
Feifel
Hermann
H
Gram
Peter
P
Hiestand
Ute
U
Manning
Romain
R
Wolf
Alfred G
AG
Zimmerlin
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases