title: SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Arthritis and Bone Metabolism, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com
authors.forename: Laszlo
authors.initials: L
authors.lastname: Revesz
authors.forename: Ernst
authors.initials: E
authors.lastname: Blum
authors.forename: Franco E
authors.initials: FE
authors.lastname: Di Padova
authors.forename: Thomas
authors.initials: T
authors.lastname: Buhl
authors.forename: Roland
authors.initials: R
authors.lastname: Feifel
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Peter
authors.initials: P
authors.lastname: Hiestand
authors.forename: Ute
authors.initials: U
authors.lastname: Manning
authors.forename: Gerard
authors.initials: G
authors.lastname: Rucklin
mesh_terms: 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*
chemical_list: D001577:Benzophenones; D004791:Enzyme Inhibitors; D011725:Pyridines; C047723:benzophenone; D048051:p38 Mitogen-Activated Protein Kinases