Benzothiazole based inhibitors of p38alpha MAP kinase.
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.
Liu
Chunjian
C
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. chunjian.liu@bms.com
Lin
James
J
Pitt
Sidney
S
Zhang
Rosemary F
RF
Sack
John S
JS
Kiefer
Susan E
SE
Kish
Kevin
K
Doweyko
Arthur M
AM
Zhang
Hongjian
H
Marathe
Punit H
PH
Trzaskos
James
J
Mckinnon
Murray
M
Dodd
John H
JH
Barrish
Joel C
JC
Schieven
Gary L
GL
Leftheris
Katerina
K
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
D052160:Benzothiazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14; C005465:benzothiazole