title: Benzothiazole based inhibitors of p38alpha MAP kinase.
abstract: Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. chunjian.liu@bms.com
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.forename: Rosemary F
authors.initials: RF
authors.lastname: Zhang
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.forename: James
authors.initials: J
authors.lastname: Trzaskos
authors.forename: Murray
authors.initials: M
authors.lastname: Mckinnon
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D018360:Crystallography, X-Ray; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14; C005465:benzothiazole