Improvement of cardiovascular remodelling by chymase inhibitor

Jin, Denan

doi:10.1111/1440-1681.12549

Cited by 26 publications

(22 citation statements)

References 77 publications

(190 reference statements)

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“…Chymase is a chymotrypsin‐like serine protease that is secreted locally in response to tissue injury from activated mast cells and other cells, such as cardiomyocytes . Chymase is activated only after secretion and appears to be involved in the local generation/activation of pro‐fibrotic factors such as angiotensin (Ang) II, transforming growth factor β, and matrix metalloproteinases, all contributing to adverse cardiac remodeling after MI …”

mentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers

Kanefendt

Thuß

Becka

et al. 2018

Clinical Pharm in Drug Dev

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The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.

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confidence: 99%

Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers

Kanefendt

Thuß

Becka

et al. 2018

Clinical Pharm in Drug Dev

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“…259 Also, inhibition of chymase, an angiotensin II-forming enzyme that activates MMP-9, has been proposed as a potentially target to prevent CV diseases. 260 Therefore, the therapeutic removal of senescent cells and reduction of MMP and chymase activities may be an attractive approach to improve CV aging and extend healthy lifespan.…”

Section: Potential Interventions That Retard Cardiovascular Agingmentioning

confidence: 99%

Pharmacological Strategies to Retard Cardiovascular Aging

Alfaras

Germanio

Bernier

et al. 2016

Circulation Research

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Aging is the major risk factor for cardiovascular diseases (CVD), which are the leading cause of death in the United States. Traditionally, the effort to prevent CVD has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat CVD. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the pro-longevity benefits of various therapeutic strategies that support cardiovascular health.

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“…A clinical case for studying the chymase/Ang II axis as an additional (potentially additive) target for inhibition of local RAS comes from preclinical studies of chymase inhibition. [94••, 95] In addition, combined chymase and ACE inhibition, compared to ACE inhibition alone, provides an added benefit in terms of left ventricular function, adverse cardiac remodeling and survival after myocardial infarction in hamsters. [46••]…”

Section: Introductionmentioning

confidence: 99%

Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease

et al. 2017

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Purpose of review Drugs targeting the renin-angiotensin system (RAS), namely angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious Ang II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). Recent findings Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently-discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from [Ang-(1-12)]. The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. [Ang-(1-12)] expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Summary Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously-unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the [Ang-(1-12)]/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

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Improvement of cardiovascular remodelling by chymase inhibitor

Cited by 26 publications

References 77 publications

Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers

Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers

Pharmacological Strategies to Retard Cardiovascular Aging

Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease

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