Abstract
We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-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.
MeSH terms
-
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
-
Binding Sites
-
Cell Line
-
Computer Simulation
-
Humans
-
Protein Binding
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Rats
-
Structure-Activity Relationship
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Amides
-
Anti-Inflammatory Agents, Non-Steroidal
-
Protein Kinase Inhibitors
-
p38 Mitogen-Activated Protein Kinases