p38α mitogen-activated protein kinase inhibitors, a patent review (2005 – 2011)

Abstract

Introduction: Since the first biological factor that neutralized tumor necrosis (TNF)-α was brought to the market, there has been a desperate search for small molecules with the same efficacy in therapy of inflammatory disorders. One of the most promising targets is p38α mitogen-activated protein (MAP) kinase. This enzyme is a key player in a vast number of inflammatory and autoimmune processes.

Areas covered: Almost every international company doing research in drug discovery is or was involved in the development of compounds that inhibit p38α MAP kinase. Herein their patents and the corresponding publications are summarized.

Expert opinion: In the last few years, compounds have become more potent and more selective, for example, by induction of the so-called glycine flip. Furthermore, some companies are striving for selectivity with respect to isoforms. The increasing availability of rapid screening services, which include more than 400 kinases, has encouraged companies to reconsider traditional approaches. The most promising approach appears to be the development of linear binding molecules that feature a carbonyl oxygen that can enforce the glycine flip. Furthermore, recent projects increasingly target new fields of application, for example, pulmonary diseases. This might be the most important trend of the past few years.

Keywords:

• (TNF)-α
• allosteric inhibitor
• asthma
• BIRB-796
• competitive inhibitor
• COPD
• cytokine
• DFG-out
• GW-856553
• inflammatory diseases
• intracellular target
• kinase
• neuropathic pain
• p38 MAP kinase
• PH-797804
• pulmonary diseases
• rheumatoid arthritis
• SB-681323
• SCIO-469
• VX-745

Acknowledgment

The authors would like to thank W Albrecht for creating Figure 1.

Notes

This box summarizes key points contained in the article.