An updated patent review of p38 MAP kinase inhibitors (2014-2019)

ABSTRACT

Introduction: During the first half of the last decade the p38 MAP kinase family was a very popular target in academic as well as industrial research programs. Many attempts to achieve marketing authorization for a p38 MAPK inhibitor for the treatment of pro-inflammatory diseases, like rheumatoid arthritis (RA), failed at the state of clinical trials, mostly due to selectivity and/or toxicity issues.

Areas covered: Herein, the patents and corresponding publications of international companies, universities and other research institutions, which focus on the development, identification and optimization of new selective p38 inhibitors and their fields of use are summarized.

Expert opinion: p38 MAP kinase inhibitors are a mature field with many pre-clinically validated structural classes, more than 20 candidates in clinical trials but still (except the weak and unselective p38 inhibitor pirfenidone) no approved drug. Big Pharma hasn’t contributed much to the patents of the last five years but remarkable contribution have come from academic environment or small biotech companies. Three general punchlines of innovation have shown up. Tailor-made molecules with properties for local application, mainly type-II (Urea-type) inhibitors for lung- or skin diseases, isoform p38γ,δ-selective inhibitors for the treatment of cutaneous t-cell lymphoma (CTCL) and substrate-specific inhibitors (e.g. p38/MK2).

KEYWORDS:

• Allosteric inhibitor
• competitive inhibitor
• DFG-out
• downstream effectors
• p38 MAPK
• p38/MK2 inhibitor

Article highlights

• New proposed allosteric binding mode of a novel class of p38 MAPK inhibitors.

• Evaluation of smaller companies and research centers with promising target-orientated strategies.

• New trends in the field of application of p38 MAPK inhibitors for novel indications, including a great change for the treatment of some orphan diseases.

• New trends in the field of drug combination, with special attention to cancer therapy.

• Expert opinion by p38 MAPK specialist.

Acknowledgments

The authors thank the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2180 – 390900677. Moreover, we gratefully thank Ms. Kristine Schmidt for proof reading the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.