title: The design and synthesis of novel alpha-ketoamide-based p38 MAP kinase inhibitors.
abstract: 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.
authors.affiliation: Drug Discovery, Kémia, Inc., 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA. catalaba@hotmail.com
authors.forename: Antonio Garrido
authors.initials: AG
authors.lastname: Montalban
authors.forename: Erik
authors.initials: E
authors.lastname: Boman
authors.forename: Chau-Dung
authors.initials: CD
authors.lastname: Chang
authors.forename: Susana Conde
authors.initials: SC
authors.lastname: Ceide
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: David
authors.initials: D
authors.lastname: Dalesandro
authors.forename: Nancy G J
authors.initials: NG
authors.lastname: Delaet
authors.forename: Eric
authors.initials: E
authors.lastname: Erb
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ernst
authors.forename: Andrew
authors.initials: A
authors.lastname: Gibbs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kahl
authors.forename: Linda
authors.initials: L
authors.lastname: Kessler
authors.forename: Jan
authors.initials: J
authors.lastname: Lundström
authors.forename: Stephen
authors.initials: S
authors.lastname: Miller
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Robert
authors.initials: R
authors.lastname: Sullivan
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Larson
mesh_terms: 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
chemical_list: D000577:Amides; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases