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Recent Advances in Cardiovascular Drug Discovery and Development

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 18473

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Prof. Dr. Grzegorz Grześk

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Department of Cardiology and Clinical Pharmacology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 75 Ujejskiego St., 85-168 Bydgoszcz, Poland
Interests: clinical and experimental pharmacology; cardiovascular pharmacology; internal medicine; en-dothelial function; vascular smooth muscle function; direct oral anticoagulants; therapeutic drug monitoring; antiplatelets agents
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Alicja Nowaczyk

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Guest Editor

Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland
Interests: organic and medicinal chemistry; computational chemistry and molecular modeling of GAT, MAT, VGIC; predictive modelling of detailed mechanisms of action and pharmacological effec-tiveness of biologically active compounds and chemical reaction pathways; neuropharmacology; cardiovascular; safety pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The therapeutic management of cardiac diseases is changing rapidly. While at the end of the 20th century, mainly symptomatic therapies were dominant, in recent years activities aimed at modifying the metabolism of cells or influencing more and more interesting signalling pathways have become the attitude. As new discoveries are made, new options are introduced into routine clinical management.

At the same time, there are new challenges, for example, better options for patients treated for heart failure or completely new problems, such as the need to treat complications after COVID-19 infection.

In such a situation, a significant acceleration of the search for new indications for known drugs, and new more effective as-yet-unknown indications, new pathways, and modulating agents that may be beneficial in therapy. Thus, research activities begin with molecular chemistry and end with evaluation in randomized clinical trials.

There are many options, and the search for the best therapeutic options becomes one of the greatest challenges in the coming years.

Hence, the purpose of this Special Issue of Molecules is to gather knowledge and advancements including clinical, translational, and preclinical evaluations of active cardiovascular compounds.

Prof. Dr. Grzegorz Grześk
Prof. Dr. Alicja Nowaczyk
Guest Editors

Manuscript Submission Information

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Keywords

mechanism of action
clinical, translational, and preclinical evaluations of active cardiovascular compounds
molecular modeling
structural analysis
drug repurposing
synthesis
safety pharmacology
therapeutic drug monitoring
current pharmacological interventions in cardiovascular system
novel and promising therapeutic options

Published Papers (7 papers)

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Research

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18 pages, 4204 KiB

Open AccessArticle

Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation

by Wenqi Li, Shuwen Zhu, Jing Liu, Zhigang Liu, Honggang Zhou, Qianyi Zhang, Yue Yang, Li Chen, Xiaowei Guo, Tiantian Zhang, Lingxin Meng, Dan Chai, Guodong Tang, Xiaohe Li and Cheng Yang

Molecules 2023, 28(16), 6035; https://doi.org/10.3390/molecules28166035 - 12 Aug 2023

Cited by 1 | Viewed by 1253

Abstract

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton’s tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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15 pages, 1630 KiB

Open AccessArticle

The Effect of PCSK9 Inhibition on the Stabilization of Atherosclerotic Plaque Determined by Biochemical and Diagnostic Imaging Methods

by Marcin Basiak, Marcin Hachula, Michal Kosowski, Grzegorz Machnik, Mateusz Maliglowka, Maria Dziubinska-Basiak, Robert Krysiak and Boguslaw Okopien

Molecules 2023, 28(15), 5928; https://doi.org/10.3390/molecules28155928 - 07 Aug 2023

Cited by 5 | Viewed by 1727

Abstract

Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of atherosclerotic plaque instability (MRI). Cytokines such as osteopontin, osteoprotegerin, and metalloproteinase 9 could be used as the most recent markers to identify and track the efficacy of anti-atherosclerotic therapy. Patients with USG and MRI-verified unstable atherosclerotic plaque were included in the study. Biomarker concentrations were measured and compared before and after PCSK9 inhibitor therapy. Additionally, concentrations prior to treatment were correlated with MRI images of the carotid artery. After treatment with alirocumab, the concentrations of MMP-9 (p < 0.01) and OPN, OPG (p < 0.05) decreased significantly. Furthermore, the results of OPN, OPG, and MMP 9 varied significantly depending on the type of atherosclerotic plaque in the MRI assay. In stable atherosclerotic plaques, the concentrations of OPN and OPG were greater (p < 0.01), whereas the concentration of MMP9 correlated with the instability of the plaque (p < 0.05). We demonstrated, probably for the first time, that alirocumab therapy significantly decreased the serum concentration of atherosclerotic plaque markers. In addition, we demonstrated the relationship between the type of atherosclerotic plaque as determined by carotid MRI and the concentration of these markers. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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12 pages, 3330 KiB

Open AccessArticle

Beta-Blocker Separation on Phosphodiester Stationary Phases—The Application of Intelligent Peak Deconvolution Analysis

by Oktawia Kalisz, Mikołaj Dembek, Sylwia Studzińska and Szymon Bocian

Molecules 2023, 28(7), 3249; https://doi.org/10.3390/molecules28073249 - 05 Apr 2023

Viewed by 1208

Abstract

Beta-blockers are a class of medications predominantly used to manage abnormal heart rhythms. They are also widely used to treat high blood pressure. From the liquid chromatography separation point of view, beta-blockers are interesting molecules due to their hydrophobic–hydrophilic properties. Thus, the study aimed to investigate the beta-blocker separation selectivity on four phosphodiester stationary phases in reversed-phase liquid chromatography (RP LC) and hydrophilic interactions liquid chromatography (HILIC). On tested stationary phases, beta-blockers provide retention in both chromatographic systems, RP LC and HILIC. Additionally, it was found that cation-exchange mechanisms have a significant contribution to retention. Separations were enhanced by applying ChromSword software for gradient optimization and Intelligent Peak Deconvolution Analysis to separate unseparated peaks digitally. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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12 pages, 2503 KiB

Open AccessArticle

SGLT2 Inhibitors May Restore Endothelial Barrier Interrupted by 25-Hydroxycholesterol

by Agnieszka Pawlos, Marlena Broncel, Ewelina Woźniak, Łukasz Markiewicz, Agnieszka Piastowska-Ciesielska and Paulina Gorzelak-Pabiś

Molecules 2023, 28(3), 1112; https://doi.org/10.3390/molecules28031112 - 22 Jan 2023

Cited by 2 | Viewed by 1800

Abstract

SGLT2 (Sodium-glucose Cotransporter-2) inhibitors are newer glucose-lowering drugs with many cardiovascular benefits that are not fully understood yet. Endothelial integrity plays a key role in cardiovascular homeostasis. 25-hydroxycholesterol (25-OHC), which is a proatherogenic stimuli that impairs endothelial barrier functions. VE-cadherin is an endothelial-specific protein crucial in maintaining endothelial integrity. The aim of this study was to assess the influence of SGLT2i on the integrity of endothelial cells interrupted by 25-OHC. We also aimed to evaluate whether this effect is associated with changes in the levels of VE-cadherin. We pre-incubated HUVECs with 10 μg/mL of 25-hydroxycholesterol (25-OHC) for 4 h and then removed it and incubated endothelial cells with 1 μM of empagliflozin, 1 μM canagliflozin, or 1 μM dapagliflozin for 24 h. The control group included HUVECs cultured with the medium or with 25-OHC 10 μg/mL. The integrity of endothelial cells was measured by the RTCA-DP xCELLigence system, and VE-cadherin was assessed in confocal microscopy. Our results show that SGLT2 inhibitors significantly increase endothelial integrity in comparison to medium controls, and they improve endothelial cell integrity interrupted by 25-OHC. This effect is associated with significant improvements in VE-cadherin levels. SGLT2i: empagliflozin, canagliflozin, and dapagliflozin have a beneficial effect on the endothelial cell integrity and VE-cadherin levels reduced by 25-OHC. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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29 pages, 1297 KiB

Open AccessReview

The Pleiotropic Role of Extracellular ATP in Myocardial Remodelling

by Suhaini Sudi, Fiona Macniesia Thomas, Siti Kadzirah Daud, Dayang Maryama Ag Daud and Caroline Sunggip

Molecules 2023, 28(5), 2102; https://doi.org/10.3390/molecules28052102 - 23 Feb 2023

Viewed by 2240

Abstract

Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection. This review outlines the sources of ATP released under physiological and pathological stress and its cell-specific mechanism of action. We further highlight a series of cardiovascular cell-to-cell communications of extracellular ATP signalling cascades in cardiac remodelling, which can be seen in hypertension, ischemia/reperfusion injury, fibrosis, hypertrophy, and atrophy. Finally, we summarize current pharmacological intervention using the ATP network as a target for cardiac protection. A better understanding of ATP communication in myocardial remodelling could be worthwhile for future drug development and repurposing and the management of cardiovascular diseases. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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14 pages, 1566 KiB

Open AccessReview

Soluble Guanylyl Cyclase Activators—Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension

by Grzegorz Grześk, Adrianna Witczyńska, Magdalena Węglarz, Łukasz Wołowiec, Jacek Nowaczyk, Elżbieta Grześk and Alicja Nowaczyk

Molecules 2023, 28(2), 861; https://doi.org/10.3390/molecules28020861 - 15 Jan 2023

Cited by 8 | Viewed by 3761

Abstract

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3′-5′—guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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28 pages, 3979 KiB

Open AccessReview

Acetylsalicylic Acid–Primus Inter Pares in Pharmacology

by Łukasz Fijałkowski, Magdalena Skubiszewska, Grzegorz Grześk, Frankline Kiptoo Koech and Alicja Nowaczyk

Molecules 2022, 27(23), 8412; https://doi.org/10.3390/molecules27238412 - 01 Dec 2022

Cited by 7 | Viewed by 5388

Abstract

Acetylsalicylic acid (ASA) is one of the first drugs to be obtained by synthesis while being the most used. It has experienced the longest lasting commercial success and is considered the most popular drug of the modern era. ASA, originally used as an anti-inflammatory medication, nowadays is predominantly used as an antiplatelet agent for prophylaxis in cardiac patients. Many studies show that the benefits of using ASA far outweigh the potential risk of side effects. With particular emphasis on the possibility of ASA repositioning for new therapies, extending the indications for use beyond the diseases from the spectrum of atherosclerotic diseases, such as cancer, requires shifting the benefit–risk ratio, although very good, even more towards safety. Interesting activities consisting not only of changing the formulation but also modifying the drug molecule seem to be an important goal of the 21st century. ASA has become a milestone in two important fields: pharmacy and medicine. For a pharmacist, ASA is a long-used drug for which individual indications are practically maintained. For a doctor, acetylsalicylic acid is primarily an antiplatelet drug that saves millions of lives of patients with coronary heart disease or after a stroke. These facts do not exempt us from improving therapeutic methods based on ASA, the main goal of which is to reduce the risk of side effects, as well as to extend effectiveness. Modified acetylsalicylic acid molecules already seem to be a promising therapeutic option. Full article

(This article belongs to the Special Issue Recent Advances in Cardiovascular Drug Discovery and Development)

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