Serine protease inhibitors to treat inflammation: a patent review (2011-2016)

ABSTRACT

Introduction: Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation.

Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016.

Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammatory arthritis. Several serine proteases were selected for their contribution to inflammatory diseases and significant efforts that are spread to develop inhibitors. Strategies developed for inhibitor identification consist on either peptide-based inhibitor derived from endogenous protein inhibitors or small-organic molecules. It is also worth noting that among the recent patents on serine protease inhibitors related to inflammation a significant number are related to retinal vascular dysfunction and skin diseases.

KEYWORDS:

• Serine proteases
• inflammation
• therapeutical inhibitors
• kallikreins
• plasmin
• neutrophil elastase
• skin inflammation
• lung inflammation
• gastrointestinal inflammation

Article highlights

• In this review, we focus on the serine proteases involved in inflammatory diseases

• Selected inhibitor patents are reported for the 2011-2016 period with a special emphasis for kallikreins, plasmin and neutrophil elastase

• The inhibitors can be divided in two categories: (i) heterocycles and (ii) peptidic or peptidomimetic entities inspired from substrates or macromolecular natural inhibitors

• The most successful inhibitor group is this of heterocycles that includes: triazoles, benzylamine, benzoxazinones, pyrroles, coumarins.

• Skin inflammatory diseases (Netherton Syndrome, atopic dermatitis, psoriasis, rosacea) and lung inflammation constitute among the most dynamic therapeutical areas within the analyzed time period

• Several preclinical studies on serine protease inhibitors were performed in the context of joint diseases (neutrophil elastase)

• GI inflammatory diseases (Crohn’s disease, ulcerative colitis) are under consideration for the targeting of serine proteases (trypsin-like proteases).

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Additional information

Funding

The authors are grateful to Université Pierre et Marie Curie (UPMC), Institut National pour la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) for research founding and to the French Ministry of Research and Education for F. S. PhD fellowship. We also thank Adrien Bussard from the SATTLetch for his kind help with patent search tools.