Biphenyl amide p38 kinase inhibitors 2: Optimisation and SAR

• Published in: Bioorganic & medicinal chemistry 2008, Vol.18 (1), p.324-328
• Main Authors: Angell, Richard M., Angell, Tony D., Bamborough, Paul, Brown, David, Brown, Murray, Buckton, Jacky B., Cockerill, Stuart G., Edwards, Chris D., Jones, Katherine L., Longstaff, Tim, Smee, Penny A., Smith, Kathryn J., Somers, Don O., Walker, Ann L., Willson, Malcolm
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Binding mode; Biological and medical sciences; biphenyl amide; biphenyl amides; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacokinetics; Biphenyl Compounds - pharmacology; Bones, joints and connective tissue. Antiinflammatory agents; BPA; BPAs; Crystallography, X-Ray; CSBP; Inhibitors; Kinase selectivity; MAP kinase; Medical sciences; Models, Molecular; Molecular Conformation; Oxadiazoles - chemistry; Oxadiazoles - pharmacokinetics; Oxadiazoles - pharmacology; p38; p38 kinase; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - chemistry; p38 Mitogen-Activated Protein Kinases - metabolism; p38α; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - pharmacology; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein kinase X-ray structure; Rats; Structure-Activity Relationship; Structure-based drug design
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.10.043

Structure–activity relationships of the biphenyl amide (BPA) series against p38α are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a selective compound showing oral activity in an in vivo disease model. The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure–activity relationships of the series against p38α are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.