The design and synthesis of novel α-ketoamide-based p38 MAP kinase inhibitors

The design and synthesis of novel α-ketoamide-based p38 inhibitors is reported. 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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2008-03, Vol.18 (6), p.1772-1777
Hauptverfasser:	Montalban, Antonio Garrido, Boman, Erik, Chang, Chau-Dung, Ceide, Susana Conde, Dahl, Russell, Dalesandro, David, Delaet, Nancy G.J., Erb, Eric, Ernst, Justin T., Gibbs, Andrew, Kahl, Jeffrey, Kessler, Linda, Lundström, Jan, Miller, Stephen, Nakanishi, Hiroshi, Roberts, Edward, Saiah, Eddine, Sullivan, Robert, Wang, Zhijun, Larson, Christopher J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Adenosine Triphosphate - metabolism Allosteric Site Amides - chemical synthesis Amides - chemistry Amides - pharmacokinetics Amides - pharmacology Animals Antiinflammatory Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cells, Cultured Crystallography, X-Ray Cytokines Drug Design Drug-like Humans Ketoamides Lipopolysaccharides - pharmacology Medical sciences Models, Molecular Molecular Structure Monocytes - cytology Monocytes - drug effects p38 MAP kinase p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors p38 Mitogen-Activated Protein Kinases - metabolism Pharmacology. Drug treatments Phosphorylation - drug effects Protein Binding Protein Conformation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Rats SAR Structure-Activity Relationship Tumor Necrosis Factor-alpha - metabolism
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Beschreibung
Zusammenfassung:	The design and synthesis of novel α-ketoamide-based p38 inhibitors is reported. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.02.033