Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018)

ABSTRACT

Introduction: Chymase is primarily found in mast cells (MCs), fibroblasts, and vascular endothelial cells. MC chymase is released into the extracellular interstitium in response to inflammatory signals, tissue injury, and cellular stress. Among many functions, chymase is a major extravascular source for angiotensin II (Ang II) generation. Several recent pre-clinical and a few clinical studies point to the relatively unrecognized fact that chymase inhibition may have significant therapeutic advantages over other treatments in halting progression of cardiac and vascular disease.

Area covered: The present review covers patent literature on chymase inhibitors for the treatment of cardiac diseases registered between 2010 and 2018.

Expert opinion: Increase in cardiac MC number in various cardiac diseases has been found in pathological tissues of human and experimental animals. Meta-analysis data from large clinical trials employing angiotensin-converting enzyme (ACE) inhibitors show a relatively small risk reduction of clinical cardiovascular endpoints. The disconnect between the expected benefit associated with Ang II blockade of synthesis or activity underscores a greater participation of chymase compared to ACE in forming Ang II in humans. Emerging literature and a reconsideration of previous studies provide lucid arguments to reconsider chymase as a primary Ang II forming enzyme in human heart and vasculature.

KEYWORDS:

• Mast cells
• serine protease
• chymase
• chymase inhibitors
• angiotensin-converting enzyme
• angiotensin II
• angiotensin I
• angiotensin-(1-12)
• renin
• metabolism
• renin-angiotensin system
• angiotensinogen

Article highlights

• We review the role of mast cell chymases in the progression of cardiovascular disease in humans.

• We underscore how species differences in chymase genes and hydrolytic activity of chymase isoforms influences the actions of MC proteases.

• We document what US patents have been filed for the use of orally active chymase inhibitors between 2010 and to-date.

This box summarizes key points contained in the article.

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 work was supported by grant from the National Heart, Lung and Blood Institute of the National Institutes of Health [P01 HL-051952]