Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes

• Published in: Bioorganic & medicinal chemistry 2008-08, Vol.18 (15), p.4433-4437
• Main Authors: Angell, Richard M., Angell, Tony D., Bamborough, Paul, Bamford, Mark J., Chung, Chun-wa, Cockerill, Stuart G., Flack, Stephen S., Jones, Katherine L., Laine, Dramane I., Longstaff, Timothy, Ludbrook, Steve, Pearson, Rosannah, Smith, Kathryn J., Smee, Penny A., Somers, Don O., Walker, Ann L.
• Format: Article
• Language: English
• Subjects: Amides - blood; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amino Acids - genetics; Amino Acids - metabolism; Binding mode; Binding Sites; Biological and medical sciences; Biphenyl amide; Biphenyl Compounds - blood; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Combinatorial Chemistry Techniques; Crystallography, X-Ray; DFG-out; Drug Design; Kinetics; Lipopolysaccharides - pharmacology; MAP kinase; Medical sciences; Miscellaneous; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Molecular Conformation; Molecular Structure; Naphthalenes - pharmacology; p38 Kinase inhibitors; Pharmacology. Drug treatments; Protein kinase X-ray structure; Pyrazoles - pharmacology; Selectivity; Structure-Activity Relationship
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.06.028

The biphenyl amides (BPAs) are a series of p38α MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38α conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.