Screening of Synthetic Heterocyclic Compounds as Antiplatelet Drugs

Background: Antiplatelet drugs represent the keystone in the treatment and prevention of diseases of ischemic origin, including coronary artery disease. The current palette of drugs represents efficient modalities in most cases, but their effect can be limited in certain situations or associated with specific side effects. In this study, representatives of compounds selected from series having scaffolds with known or potential antiplatelet activity were tested. These compounds were previously synthetized by us, but their biological effects have not yet been reported. Objective: The aim of this study was to examine the antiplatelet and anticoagulation properties of selected compounds and determine their mechanism of action. Methods: Antiplatelet activity of compounds and their mechanisms of action were evaluated using human blood by impedance aggregometry and various aggregation inducers and inhibitors and compared to appropriate standards. Cytotoxicity was tested using breast adenocarcinoma cell cultures and potential anticoagulation activity was also determined. Results: In total, four of 34 compounds tested were equally or more active than the standard antiplatelet drug acetylsalicylic acid (ASA). In contrast to ASA, all 4 active compounds decreased platelet aggregation triggered not only by collagen, but also partly by ADP. The major mechanism of action is based on antagonism at thromboxane receptors. In higher concentrations, inhibition of thromboxane synthase was also noted. In contrast to ASA, the tested compounds did not block cyclooxygenase-1. Conclusion: The most active compound, 2-amino-4-(1H-indol-3-yl)-6-nitro-4H-chromene-3-carbonitrile (2-N), which is 4-5x times more potent than ASA, is a promising compound for the development of novel antiplatelet drugs.

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Chemistry, Biological Effects, and Mechanism of Action of Plant Growth Substances

Plant Growth Substances ◽

10.1007/978-1-4757-2451-6_3 ◽

1996 ◽

pp. 45-103 ◽

Cited By ~ 1

Author(s):

Richard N. Arteca

Keyword(s):

Plant Growth ◽

Mechanism Of Action ◽

Biological Effects ◽

Growth Substances ◽

Plant Growth Substances

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Identification of Anti-malarial Drug Candidate Inhibitors using Ultra-high Throughput Screening Methods and Subsequent Mechanism of Action Studies Aimed at the Treatment and Prevention of Plasmodium falciparum

10.14264/uql.2019.548 ◽

2019 ◽

Author(s):

Timothy Patrick Spicer

Keyword(s):

Plasmodium Falciparum ◽

High Throughput ◽

Mechanism Of Action ◽

High Throughput Screening ◽

Drug Candidate ◽

Screening Methods ◽

Treatment And Prevention

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Lithium - Pharmacological and Toxicological Aspects: The Current State of the Art

Current Medicinal Chemistry ◽

10.2174/0929867325666180904124733 ◽

2020 ◽

Vol 27 (3) ◽

pp. 337-351 ◽

Cited By ~ 7

Author(s):

Branislava Medić ◽

Marko Stojanović ◽

Bojan V. Stimec ◽

Nevena Divac ◽

Katarina Savić Vujović ◽

...

Keyword(s):

Mechanism Of Action ◽

Glycogen Synthase ◽

Tissue Injury ◽

Current Knowledge ◽

Biological Effects ◽

Therapeutic Index ◽

Adjunctive Treatment ◽

Renal Diseases ◽

Protective Effects ◽

Organ Systems

: Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in the pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3β) which is included in the regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc. : Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well as clinical studies in order to a precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning the pharmacological and toxicological effects of lithium.

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Effect of oral antiplatelet agents on major bleeding in users of coumarins

Thrombosis and Haemostasis ◽

10.1160/th08-05-0290 ◽

2008 ◽

Vol 100 (12) ◽

pp. 1076-1083 ◽

Cited By ~ 19

Author(s):

Olaf H. Klungel ◽

Patrick C. Souverein ◽

Anthonius de Boer ◽

Tom Schalekamp

Keyword(s):

Major Bleeding ◽

Conditional Logistic Regression ◽

Vitamin K Antagonists ◽

Antiplatelet Agents ◽

Bleeding Risk ◽

Primary Diagnosis ◽

Antiplatelet Drugs ◽

Antiplatelet Drug ◽

Concurrent Use ◽

Increased Risk

SummaryTreatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data froma Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI).We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2–6.9 and OR 1.6, 95% CI 1.3–1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0–2.3 and OR 1.8, 95 % CI 1.0–3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

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Biochanin A, the Most Potent of 16 Isoflavones, Induces Relaxation of the Coronary Artery Through the Calcium Channel and cGMP-dependent Pathway

Planta Medica ◽

10.1055/a-1158-9422 ◽

2020 ◽

Vol 86 (10) ◽

pp. 708-716

Author(s):

Thomas Migkos ◽

Jana Pourová ◽

Marie Vopršalová ◽

Cyril Auger ◽

Valérie Schini-Kerth ◽

...

Keyword(s):

Coronary Arteries ◽

Mechanism Of Action ◽

Biochanin A ◽

Dependent Manner ◽

Major Mechanism ◽

Camp Pathway ◽

Clinical Interest ◽

Series Of Experiments ◽

Dose Dependent ◽

Dependent Pathway

AbstractThe dietary intake of flavonoids seems to be inversely related to cardiovascular mortality. The consumption of isoflavonoids is increasing in the general population, especially due to the use of food supplements and a variety of isoflavonoid-rich foods. However, detailed studies on the vascular influence of individual pure isoflavonoids are mostly missing. For this study, 16 isoflavonoids were initially screened for their vasorelaxant properties on rat aortas. The 2 most potent of them, biochanin A and glycitein, were further tested for the mechanism of action on porcine coronary arteries. They both induced an endothelium independent vascular relaxation, with EC50 below 6 and 17 µM, respectively. Biochanin A, but not glycitein, was able to block the vasoconstriction caused by KCl, CaCl2, serotonin, and U46619 in a dose-dependent manner. Another series of experiments suggested that the major mechanism of action of biochanin A was the inhibition of L-type calcium channels. Moreover, biochanin A in relatively small concentrations (2 – 4 µM) interfered with the cGMP, but not cAMP, pathway in isolated coronary arteries. These results indicate that some isoflavonoids, in particular biochanin A, are able to have vasodilatory effects in micromolar concentrations, which is of potential clinical interest for the management of cardiovascular pathologies.

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Biological Effects of c-Mer Receptor Tyrosine Kinase in Hematopoietic Cells Depend on the Grb2 Binding Site in the Receptor and Activation of NF-κB

Molecular and Cellular Biology ◽

10.1128/mcb.19.2.1171 ◽

1999 ◽

Vol 19 (2) ◽

pp. 1171-1181 ◽

Cited By ~ 60

Author(s):

Maria-Magdalena Georgescu ◽

Kathrin H. Kirsch ◽

Tomoyuki Shishido ◽

Chen Zong ◽

Hidesaburo Hanafusa

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Transcriptional Activation ◽

B Lymphocyte ◽

Biological Effects ◽

Leukemia Cell ◽

Lymphoid Cells ◽

Mutant Receptor ◽

Major Mechanism ◽

The Difference

ABSTRACT The c-Mer receptor tyrosine kinase (RTK) is most closely related to chicken c-Eyk and belongs to the Axl RTK subfamily. Although not detected in normal lymphocytes, c-Mer is expressed in B- and T-cell leukemia cell lines, suggesting an association with lymphoid malignancies. To gain an understanding of the role of this receptor in lymphoid cells, we expressed in murine interleukin-3 (IL-3)-dependent Ba/F3 pro-B-lymphocyte cells a constitutively active receptor, CDMer, formed from the CD8 extracellular domain and the c-Mer intracellular domain. Cells transfected with a plasmid encoding the CDMer receptor became IL-3 independent. When tyrosine (Y)-to-phenylalanine (F) mutations were introduced into c-Mer, only the Y867 change significantly reduced the IL-3-independent cell proliferation. The Y867 residue in the CDMer receptor mediated the binding of Grb2, which recruited the p85 phosphatidylinositol 3-kinase (PI 3-kinase). Despite the difference in promotion of proliferation, both the CDMer and mutant F867 receptors activated Erk in transfected cells. On the other hand, we found that both transcriptional activation of NF-κB and activation of PI 3-kinase were significantly suppressed with the F867 mutant receptor, suggesting that the activation of antiapoptotic pathways is the major mechanism for the observed phenotypic difference. Consistent with this notion, apoptosis induced by IL-3 withdrawal was strongly prevented by CDMer but not by the F867 mutant receptor.

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1148 Viral dynamics modeling indicates that the major mechanism of action of HepeX-B against hepatitis B virus is acceleration of the free virus clearance

Hepatology ◽

10.1016/s0270-9139(03)81186-2 ◽

2003 ◽

Vol 38 ◽

pp. 709-709 ◽

Cited By ~ 1

Author(s):

A NEUMANN ◽

I FELDBERG ◽

R EREN ◽

S DAGAN

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Mechanism Of Action ◽

Viral Dynamics ◽

Dynamics Modeling ◽

Free Virus ◽

Major Mechanism ◽

Virus Clearance ◽

B Virus

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Prevalence and Resolution of Resistant Left Atrial Appendage Thrombus in Non-Valvular Atrial Fibrillation Patients Submitted to Percutaneous Interventions

Clinical Cardiology and Cardiovascular Interventions ◽

10.31579/2641-0419/161 ◽

2021 ◽

Vol 4 (8) ◽

pp. 01-09

Author(s):

Fabricio Vassallo

Keyword(s):

Atrial Fibrillation ◽

Mechanism Of Action ◽

Complete Resolution ◽

Left Atrial ◽

Left Atrial Appendage ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Atrial Appendage ◽

Antiplatelet Drug ◽

Diabetes Diagnosis

Introduction: Left atrial appendage (LAA) thrombus in atrial tachyarrhythmias is one of the principal causes of stroke. Prevalence and strategies to thrombus resolution has recently been described in the era of the direct oral anticoagulants (DOAC). The aim of the study was to determine the prevalence and strategies to resolve previous LAA thrombus during regular oral antithrombotic therapy in preparation to perform atrial fibrillation (AF) ablation and/or LAA closure. Methods: Between January 2011 and December 2020 we prospectively followed 23 patients (5.39%) that showed LAA thrombus formation. Persistent AF occurred in 13 (56.52%), median age 72.39 years, 15 (65.22%) females, median CHA2DS2VASC of 4.13, HASBLED of 2.28, 17 (73.91%) with hypertension, (52.17%) with coronary disease, 9 (39.13%) had priors’ thromboembolic events, 7 (30.43%) with heart failure and Diabetes. Diagnosis was by transesophageal echocardiogram (TEE) in 20 (86.96%) and the rest by computed angiotomography. Rivaroxaban was used in 11 (47.83%), Dabigatran in 6 (26.09%), 5 (21.74%) with therapeutic range Warfarin and 1 (4.34%) with Apixaban. Main strategy of treatment was to change mechanism of action of antithrombotic medication in association to an antiplatelet drug, Clopidogrel 75mg a day, and perform a TEE at 90 days after. Results: Complete resolution of the LAA thrombus was achieved in 18 (78.26%) patients in first medical therapeutic change. Of the remaining a second approach with medical therapy adjustment with off-label dose prescription associated with Clopidogrel showed complete resolution in 3 (13.04%) totalizing a success rate of 91.30% for all patients (p value of 0.001 for treatment success). The failure of the antithrombotic plus antiplatelet therapy occurred in 2 (8.7%) patients, one with LAA sludge and other with a huge thrombus in all LAA and part of left atrium. Conclusion: Modification of the mechanism of action of direct oral anticoagulants in association with Clopidogrel demonstrates to be successful in a large number of patients with previous resistant left atrial thrombus with and secure since the low adverse event rates.

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