A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis

Dearg S Brown; Andrew J Belfield; George R Brown; Douglas Campbell; Alan Foubister; David J Masters; Kurt G Pike; Wendy L Snelson; Stuart L Wells

doi:10.1016/j.bmcl.2004.08.006

A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis

Bioorg Med Chem Lett. 2004 Nov 1;14(21):5383-7. doi: 10.1016/j.bmcl.2004.08.006.

Authors

Dearg S Brown¹, Andrew J Belfield, George R Brown, Douglas Campbell, Alan Foubister, David J Masters, Kurt G Pike, Wendy L Snelson, Stuart L Wells

Affiliation

¹ AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. dearg.brown@astrazeneca.com

PMID: 15454231
DOI: 10.1016/j.bmcl.2004.08.006

Abstract

A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.

MeSH terms

Amides / chemical synthesis*
Amides / pharmacokinetics
Amides / pharmacology
Animals
Antirheumatic Agents / chemical synthesis*
Antirheumatic Agents / pharmacokinetics
Antirheumatic Agents / pharmacology
Arthritis, Rheumatoid / drug therapy
Humans
In Vitro Techniques
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Lipopolysaccharides / pharmacology
Mice
Mice, Inbred BALB C
Rats
Structure-Activity Relationship
Time Factors
Tumor Necrosis Factor-alpha / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

Amides
Antirheumatic Agents
Lipopolysaccharides
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases