Optimization of α-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site

The design and synthesis of novel α-ketoamide based p38 inhibitors is reported. We have optimized a novel series of potent p38 MAP kinase inhibitors based on an α-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (16), p.4819-4824
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, Kucharski, Jeff, Lum, Christopher, Lundström, Jan, Miller, Stephen, Nakanishi, Hiroshi, Roberts, Edward, Saiah, Eddine, Sullivan, Robert, Urban, Jan, Wang, Zhijun, Larson, Christopher J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Allosteric Site Amides - chemical synthesis Amides - chemistry Amides - pharmacology Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Antiinflammatory Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cell Line Computer Simulation Cytokines Drug-like Humans Ketoamides Medical sciences p38 MAP kinase p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors p38 Mitogen-Activated Protein Kinases - metabolism Pharmacology. Drug treatments Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Rats SAR Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	The design and synthesis of novel α-ketoamide based p38 inhibitors is reported. We have optimized a novel series of potent p38 MAP kinase inhibitors based on an α-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.06.102