Journal
EXPERT OPINION ON THERAPEUTIC PATENTS
Volume 28, Issue 11, Pages 755-764Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/13543776.2018.1531848
Keywords
Mast cells; serine protease; chymase; chymase inhibitors; angiotensin-converting enzyme; angiotensin II; angiotensin I; angiotensin-(1-12); renin; metabolism; renin-angiotensin system; angiotensinogen
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Funding
- NHLBI NIH HHS [P01 HL051952] Funding Source: Medline
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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.
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