SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity.
Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.
Revesz
Laszlo
L
Novartis Institutes for BioMedical Research, Arthritis and 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; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D001577:Benzophenones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D009055:Mouth / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001577:Benzophenones; D004791:Enzyme Inhibitors; D011725:Pyridines; C047723:benzophenone; D048051:p38 Mitogen-Activated Protein Kinases