p38 MAPK inhibitors: a patent review (2012 – 2013)

Abstract

Introduction: The p38 MAPK is a ubiquitous target in the research-based pharmaceutical industry. It plays a decisive role in the regulation of the production of proinflammatory cytokines. Since novel biological therapies have revolutionized the treatment of chronic inflammatory diseases, an intensive global search is underway for small molecules for the same application.

Areas covered: Herein, the patents and the corresponding publications of international companies, which focus on the development and identification of a new generation of small-molecule p38 inhibitors, are summarized.

Expert opinion: The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.

Keywords::

• allosteric inhibitor
• Alzheimer`s disease
• asthma
• BAY 73-4506
• BMS-582949
• cancer
• chronic obstructive pulmonary disease
• competitive inhibitor
• DFG-out
• downstream effectors
• drug combination
• dual action p38 inhibitor
• glycine flip
• inflammatory diseases
• linear binders
• non-small-cell lung carcinoma
• p38 MAPK
• p38/MK2 inhibitors
• proinflammatory cytokine
• pulmonary diseases
• rheumatoid arthritis
• TNF-α
• upstream kinase
• VX-745

Declaration of interest

The authors have no conflict of interest and have received no payment in preparation of this manuscript.

Notes

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