A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications

ABSTRACT

Introduction: Human neutrophil elastase (HNE) is involved in a variety of serious chronic diseases, especially cardiopulmonary pathologies. For this reason, the regulation of HNE activity represents a promising therapeutic approach, which is evident by the development of a number of new and selective HNE inhibitors, both in the academic and pharmaceutical environments.

Areas covered: The present review analyzes and summarizes the patent literature regarding human neutrophil elastase inhibitors for the treatment of cardiopulmonary diseases over 2014–2018.

Expert opinion: HNE is an interesting and defined target to treat various inflammatory diseases, including a number of cardiopulmonary pathologies. The research in this field is quite active, and a number of HNE inhibitors are currently in various stages of clinical development. In addition, new opportunities for HNE inhibitor development stem from recent studies demonstrating the involvement of HNE in many other inflammatory pathologies, including rheumatoid arthritis, inflammatory bowel disease, skin diseases, and cancer. Furthermore, the development of dual HNE/proteinase 3 inhibitors is being pursued as an innovative approach for the treatment of neutrophilic inflammatory diseases. Thus, these new developments will likely stimulate new and increased interest in this important therapeutic target and for the development of novel and selective HNE inhibitors.

KEYWORDS:

• Human neutrophil elastase
• elastase inhibitors
• cardiopulmonary diseases
• inflammation
• protease-antiproteases imbalance

Article highlights

• This review focuses on neutrophil elastase (NE) inhibitor patents reported in the literature over 2014-2018.

• The main application of HNE inhibitors concerns the treatment of (cardio)pulmonary inflammatory diseases; other possible uses include skin pathologies, rheumatoid arthritis, and cancer.

• This review follows the recent classification proposed for HNE inhibitors, which considers five generations, starting from biologicals (1st generation) to ‘pre-adaptive pharmacophore derived from 4th generation inhibitors’ (5th generation). Many of these compounds show picomolar activity, high selectivity, and drug-like pharmacokinetic properties.

• In this review, a systematic investigation of pharmaceutical companies working on HNE inhibitors was done. Accordingly, for each company, the most interesting results are reported. A miscellaneous from literature follows.

• Non-peptidic NE inhibitors are low-molecular-mass synthetic compounds containing nitrogen heterocycles such as pyrimidinone, pyrimidinedione, 2-pyrazinone, pyrimidine, pyridine, 4-pyridone, 2-pyridone, and pyridazine.

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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 or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grant or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are trying to develop HNE inhibitors and filed patent applications. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded in part by the National Institutes of Health IDeA Program COBRE Grant GM110732, the USDA National Institute of Food and Agriculture Hatch project 1009546, and the Montana State University Agricultural Experiment Station.