FR167653, a candidate p38 MAPK inhibitor for the treatment of rheumatoid arthritis

Approximately one in five people in the western world suffer from autoimmune diseases and an estimated 5 million individuals suffer from rheumatoid arhtritis (RA). In total it is predicted that the annual value of the market for drugs used to treat autoimmune disease will soon exceed $20 billion. The field of RA therapeutics is attracting massive interest in the wake of resurgent R&D activity that has advanced our understanding of the etiology of the disease. One target analyzed in LeadDiscovery’s state of the art analysis of RA drug discovery targets and therapeutic candidates, “Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates” is p38 mitogen-activated protein kinase (MAPK).

Recent successful development of anti-cytokine therapeutics including those that block TNF-alpha and IL-1, and more recently IL-6 has spurred research into identifying cytokine production and signaling pathways. p38 MAPK plays a pivotal role in the production of TNF and IL-1, and furthermore it is also required for the cellular response to these cytokines. The concept of developing p38 MAPK inhibitors for the treatment of RA is strong and the development of small molecule inhibitors of cytokine signaling and production holds potential advantages over existing biological therapies that prevent binding or neutralize the cytokines per se. These advantages include improved half-life and reduced immunogenicity, host immune response and cost. MAPK inhibitors have shown activity in animal models of RA and importantly effects are observed in animals with established joint inflammation as well as in animals pretreated with inhibitors prior to the induction of disease. Many companies have been involved in the development of p38 MAPK inhibitors however side effects have to date limited development.

One p38 MAPK inhibitor that has recently been investigated in the context of RA is Fujisawa Pharmaceutical’s FR167653. In their recent Arthritis & Rheumatism publication, Nishikawa et al report that FR167653 is able to almost completely prevent the swelling of joints in the collagen induced arthritis model. Perhaps more importantly when administered to rats with established arthritis, FR167653 was able to reduce paw volume towards control levels. In addition to reducing IL-1 beta and TNF-alpha, FR167653 was also able to reduce osteoclast differention and bone resorption suggesting that this p38 MAPK inhibitor is able to not only reduce inflammation but also to limit bone resorption, a key component of RA.

FR167653 has not been associated with adverse effects in animal studies to date and further toxicology studies are eagerly awaited prior to determining whether the promising therapeutic activity of this molecule warrant study under clinical conditions.

Entry date Tuesday, December 16, 2003

Adapted from Nishikawa et al, Arthritis Rheum. 2003 Sep;48(9):2670-81.