Protease activated receptor 2 (PAR2) modulators: a patent review (2010–2015)

ABSTRACT

Introduction: Protease activated receptor 2 (PAR2) is a self-activated G protein-coupled receptor that has been implicated in several diseases, including inflammatory, gastrointestinal, respiratory, metabolic diseases, cancers and others, making it an important prospective drug target. No known endogenous ligands are available for PAR2, so having potent exogenous agonists and antagonists can be helpful for studying physiological functions of PAR2.

Areas covered: This review covers agonist-, antagonist-, antibody- and pepducin-based modulators of PAR2 reported in patent applications between 2010–2015, along with their available structure-activity relationships, biological activities and potential uses for studying PAR2.

Expert opinion: In the last six years, substantial efforts were made towards developing PAR2 modulators, but most lack potency or selectivity or have poor pharmacokinetic profiles. Many PAR2 modulators were assessed by measuring Gα_q protein-mediated calcium release in cells. This may be insufficient to fully characterize ligand function, since different ligands signal through PAR2 via multiple signaling pathways. It may be feasible to develop biased ligands as drugs that can selectively modulate one or more specific signaling pathways linking PAR2 to a specific diseased state. Accordingly, potent, orally bioavailable, pathway- and receptor-selective PAR2 modulators may be an achievable goal to realizing effective drugs that can treat PAR2-mediated diseases.

KEYWORDS:

• Protease activated receptor 2 (PAR2)
• agonist
• antagonist
• antibodies
• patent

Article highlights

• PAR2 is associated with inflammatory, cardiovascular, gastrointestinal, respiratory, and metabolic diseases, highlighting it as a potentially valuable therapeutic target. It is also associated with pain, itch, wound healing, and cancer metastasis.

• Patents reporting new PAR2 agonists, antagonists, antibodies, and pepducins from 2010 to 2015 are examined.

• Structure–activity relationships (SARs) and biological activities of PAR2 modulators in vitro and in vivo as described in patents are reported.

• PAR2 modulators have been found to be beneficial for treating animal models of disease.

• Biased ligands for PAR2 show promise for modulating different signaling pathways that may be linked to different diseased states.

This box summarizes key points contained in the article.

Declaration of Interest

We thank the National Health and Medical Research Council of Australia for grants (1047759, 1084083) supporting our salaries and for a Senior Principal Research Fellowship to DP Fairlie (1027369), and acknowledge the Australian 650 Research Council for financial support (DP130100629) and for a Centre of Excellence in Advanced Molecular Imaging (CE140100011). MK Yau, J Lim, L Liu and DP Fairlie are named inventors on several patent applications involving PAR2 agonists and antagonists owned by the University of Queensland. 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.