Pathway to the Clinic: Inhibition of P38 MAP Kinase. A Review of Ten Chemotypes Selected for Development

Abstract

p38 mitogen activated protein (MAP) kinase remains the most compelling therapeutic target for oral drug intervention for a wide range of autoimmune disorders based on the central role this enzyme plays in inflammatory cell signaling. Efforts to discover inhibitors of p38 suitable for clinical investigation have continued to escalate in part due to the incredible diversity of unique chemotypes reported to inhibit the enzyme. Since 1993, at least seventeen p38 inhibitors have been reported to have entered into clinical trials. Next generation inhibitors have been disclosed with improved potency for p38 and enhanced selectivity versus other protein kinases. Over the last three years, there have been multiple reports of cytokine suppression in humans following oral administration of p38 inhibitors. These results, in addition to proof of concept studies in rheumatoid patients, have established p38 inhibition as an avenue for the future management of pro-inflammatory cytokine based diseases. This review describes the discovery at Roche of novel p38 inhibitors which have advanced into clinical trials. The pharmacology of the Roche compounds is then compared with eight chemically distinct p38 inhibitors known to have entered clinical development.

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

“…The pathway is also an interesting therapeutic opportunity for the treatment of various diseases and over 20 different p38 MAPK inhibitors have entered clinical trials (Goldstein and Gabriel, 2005). p38 was the first p38 MAPK isolated (Han et al, 1994) and is now the most thoroughly studied isoform, whereas much less is known about the other three family members.…”

Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritis

“…However, there are no marketed orally active, safe, and effective agents that act primarily to inhibit TNF␣ or IL-1␤, despite attempts to develop such compounds (1)(2)(3).…”

Effects of p38 MAP Kinase Inhibitors on the Differentiation and Maturation of Erythroid Progenitors

“…These pyridinyl imidazole-based p38α inhibitors have shown activity toward other p38 isoforms, including p38β and p38γ; however, they are more selective for inhibition of p38α, and both selectivity and inhibition profiles have been previously reported (Fabian et al 2005;Lee and Dominguez 2005). Inhibition of p38α has become an attractive yet challenging therapeutic target for treatment of chronic inflammatory disorders, such as rheumatoid arthritis, septic shock, restenosis, and inflammatory bowel syndrome (Dominguez, Powers, and Tamayo 2005), but few candidates have progressed to Phase II clinical trials due to unsuitable safety profiles noted preclinically and clinically (Goldstein and Gabriel 2005).…”