Tryptase inhibitors: a patent review

ABSTRACT

Introduction: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases.

Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases.

Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.

KEYWORDS:

• Tryptase
• mast cell
• synthetic inhibitors
• specificity
• tryptase-related diseases

Article highlights

• This paper summarized the structures, biological importance and clinical trials of tryptase inhibitors, and pointed out the development direction of these tryptase inhibitors.

• Several initial tryptase inhibitors that have been evaluated in preclinical models of asthma have significant drawbacks. So, much effort has been directed toward the identification and synthesis of a variety of new low molecular weight compounds with potential inhibitory activity and appropriate selectivity toward tryptase.

• Among the various groups of tryptase inhibitors, guanidino-based tryptase inhibitors are the most potent and hold the most potential for clinical use in inflammatory diseases.

• Clinical trials of tryptase inhibitor were focused on inflammatory diseases.

• Tryptase inhibitors have become the research hotspot to explore other tryptase-related diseases, such as hepatic fibrosis and tumor. However, it needs more clinical trials to go to market.

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

This study was sponsored by grants from the National Natural Science Foundation of China (nos. 81571568, 31340073 and 81273274); Jiangsu Province’s Key Provincial Talents Program (no. RC201170); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).