The design and synthesis of novel alpha-ketoamide-based p38 MAP kinase inhibitors.
We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.
Montalban
Antonio Garrido
AG
Drug Discovery, Kémia, Inc., 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA. catalaba@hotmail.com
Boman
Erik
E
Chang
Chau-Dung
CD
Ceide
Susana Conde
SC
Dahl
Russell
R
Dalesandro
David
D
Delaet
Nancy G J
NG
Erb
Eric
E
Ernst
Justin T
JT
Gibbs
Andrew
A
Kahl
Jeffrey
J
Kessler
Linda
L
Lundström
Jan
J
Miller
Stephen
S
Nakanishi
Hiroshi
H
Roberts
Edward
E
Saiah
Eddine
E
Sullivan
Robert
R
Wang
Zhijun
Z
Larson
Christopher J
CJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000495:Allosteric Site; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases