(Halo-benzo carbonyl)heterocyclo fused phenyl p38 kinase inhibiting agents

Abstract

Inflammatory conditions such as rheumatoid arthritis (RA) and other autoimmune diseases represent a very active area of research for the development of novel therapeutics. In the past few years, the research focus of many pharmaceutical companies and other organisations has resulted in the identification of various novel biological targets for the development of new therapies for the treatment of inflammatory diseases such as RA. This has resulted in the identification of biological agents such as infliximab (Remicade^®, Centocor, Inc.), etanercept (Enbrel^®,Immunex Corp.), adalimumab (Humira^®,Abbott Lab.) and kineret (Anakinra^®, Amgen, Inc.) that affect the TNF-α or IL1 associated pathways, for the treatment of RA and other inflammatory diseases such as psoriasis and inflammatory bowel disease (IBD). Ongoing research continues to expand the application of these agents for additional therapeutic use. In addition to the biological agents above, cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx^®, Merck & Co., Inc.) and celecoxib (Celebrex^®, Pharmacia) have also shown some efficacy for the treatment of RA. The approval of these agents for the treatment of RA has provided a validation of the role of TNF-α, IL-1 and COX-2 in the pathogenesis of RA. Although the biologicals and COX-2 inhibitors are effective, they are however limited in that they modulate a single cytokine or pathway. It is recognised that the alternate pathway delineated by p38 mitogen-activated protein kinase (MAPK) provides for a more combinatorial path for treatment of RA, as an inhibitor of p38 MAPK would not only affect TNF-α, IL-1 and other related cytokines, but also the expression of COX-2. The efforts to develop small molecule agents for p38 MAPK have not yet yielded an agent ready for the market, but several inhibitors are presently under investigation in clinical trials. While details of these studies have yet to be formally reported, two recently published studies have evaluated the effect of p38 inhibitors on the suppression of pro-inflammatory cytokines and other markers of inflammation in healthy human volunteers exposed to endotoxaemia, caused by exposure to lipopolysaccharide (LPS) [1,2].

• p38 MAPK
• rheumatoid arthritis