Thromboxane Receptors Antagonists and/or Synthase Inhibitors

2012 ◽  
pp. 261-286 ◽  
Author(s):  
Giovanni Davì ◽  
Francesca Santilli ◽  
Natale Vazzana
Keyword(s):  
Thromboxane Receptors

Screening of Synthetic Heterocyclic Compounds as Antiplatelet Drugs

2021 ◽  
Vol 17 ◽  
Author(s):  
Marcel Hrubša ◽  
Khondekar Nurjamal ◽  
Alejandro Carazo ◽  
Nayana Nayek ◽  
Jana Karlíčková ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Biological Effects ◽  
Antiplatelet Drugs ◽  
Antiplatelet Drug ◽  
Breast Adenocarcinoma ◽  
Antiplatelet Activity ◽  
Major Mechanism ◽  
Treatment And Prevention ◽  
Impedance Aggregometry ◽  
Thromboxane Receptors

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.

scholarly journals Platelets and thromboxane receptors: pivotal players in arteriogenesis: Figure 1

2015 ◽  
Vol 107 (4) ◽  
pp. 400-402 ◽  
Author(s):  
Victor W.M. Van Hinsbergh ◽  
Dimitar Tasev
Keyword(s):  
Thromboxane Receptors

BM 13.177, A SELECTIVE BLOCKER OF PLATELET AND VESSEL WALL THROMBOXANE RECEPTORS, IS ACTIVE IN MAN

The Lancet ◽  
1984 ◽  
Vol 323 (8384) ◽  
pp. 991-994 ◽  
Author(s):  
Paolo Gresele ◽  
Jef Arnout ◽  
Walter Janssens ◽  
Hans Deckmyn ◽  
Jan Lemmens ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Thromboxane Receptors ◽  
Selective Blocker

RESTING MYOCARDIAL ISCHEMIA AFTER INTRAVENOUS INFUSION OF BM 13.177, A THROMBOXANE RECEPTOR ANTAGONIST

1987 ◽  
Author(s):  
W Terres ◽  
W Kupper ◽  
C Hamm ◽  
W Bleifeld
Keyword(s):  
Myocardial Ischemia ◽  
Receptor Antagonist ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Controlled Trial ◽  
Double Blind ◽  
Thromboxane Receptor ◽  
Exertional Angina ◽  
Thromboxane Receptors ◽  
Thromboxane Receptor Antagonist

We conducted a double blind placebo controlled trial of BM 13.177, a thromboxane receptor antagonist, given intravenously in patients (PTS) with stenoses >70 % of the left anterior descending coronary artery and stable exertional angina pectoris (AP). The study had to be stopped after enrollment of 8 PTS, because 2 had developed resting AP after initiation of the study medication. Both proved to belong to the 4 PTS who had received BM 13.177 (12.5 mg/min). While in one PT, AP was mild, transient and associated with only slight decreases in coronary sinus blood flow (CSBF) and myocardial lactate extraction (MLE), in the other, AP was severe and persisted for 30 minutes in spite of antianginal therapy. Severe clinical symptoms in this PT were associated with a marked fall in MLE from +24 to -121 %. Two PTS under BM 13.177 and 4 on placebo underwent supraventricular stimulation. For both groups, no change in clinical symptoms, CSBF or MLE occured in comparison to a former control stimulation without medication. BM 13.177 led to an inhibition of ex vivo platelet aggregation induced by collagen 1 pg/ml (mean reduction in rate of aggregation by 41 %, p< 0.05), while aggregation was not influenced with collagen 5 μg/ml or ADP. This effect of BM on platelets is explained by its thromboxane receptor blocking properties. The induction of resting myocardial ischemia, however, in 2 of 4 PTS with formerly stable exertional AP may have been the result of either a coronary steal mechanism or an intrinsic stimulation of vascular thromboxane receptors, followed by coronary vasoconstriction.

Mechanism of antagonism of thromboxane receptors in vascular smooth muscle

1987 ◽  
Vol 133 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Atsuo Yanagisawa ◽  
James A. Smith ◽  
Mark E. Brezinski ◽  
Allan M. Lefer
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Thromboxane Receptors

scholarly journals Role of superoxide and thromboxane receptors in acute angiotensin II-induced vasoconstriction of rabbit vessels

2011 ◽  
Vol 300 (6) ◽  
pp. H2064-H2071 ◽  
Author(s):  
Sandra L. Pfister ◽  
Kasem Nithipatikom ◽  
William B. Campbell
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Rabbit Aorta ◽  
Arachidonic Acid Metabolite ◽  
Maximal Contraction ◽  
Nitric Oxide Synthase Inhibitor ◽  
Thromboxane Receptor ◽  
Thromboxane Receptors ◽  
Thromboxane Receptor Antagonist ◽  
Synthase Inhibitor

This study explored the hypothesis that a portion of angiotensin II-induced contractions is dependent on superoxide generation and release of a previously unidentified arachidonic acid metabolite that activates vascular smooth muscle thromboxane receptors. Treatment of rabbit aorta or mesentery artery with the thromboxane receptor antagonist SQ29548 (10 μM) reduced angiotensin II-induced contractions (maximal contraction in aorta; control vs. SQ29548: 134 ± 16 vs. 93 ± 10%). A subset of rabbits deficient in vascular thromboxane receptors also displayed decreased contractions to angiotensin II. The superoxide dismutase mimetic Tiron (30 mM) attenuated angiotensin II-induced contractions only in rabbits with functional vascular thromboxane receptors (maximal contraction in aorta; control vs. Tiron: 105 ± 5 vs. 69 ± 11%). Removal of the endothelium or treatment with a nitric oxide synthase inhibitor, nitro-l-arginine (30 μM) did not alter angiotensin II-induced contractions. Tiron and SQ29548 decreased angiotensin II-induced contractions in the denuded aortas by a similar percentage as that observed in intact vessels. The cyclooxygenase inhibitor indomethacin (10 μM) or thromboxane synthase inhibitor dazoxiben (10 μM) had no effect on angiotensin II-induced contractions indicating that the vasoconstrictor was not thromboxane. Angiotensin II increased the formation of a 15-series isoprostane. Isoprostanes are free radical-derived products of arachidonic acid. The unidentified isoprostane increased when vessels were incubated with the superoxide-generating system xanthine/xanthine oxidase. Pretreatment of rabbit aorta with the isoprostane isolated from aortic incubations enhanced angiotensin II-induced contractions. Results suggest the factor activating thromboxane receptors and contributing to angiotensin II vasoconstriction involves the superoxide-mediated generation of a 15-series isoprostane.

Magnitude of thromboxane receptor antagonism necessary for antithrombotic activity in monkeys

1989 ◽  
Vol 256 (3) ◽  
pp. H726-H734
Author(s):  
W. A. Schumacher ◽  
C. L. Heran ◽  
H. J. Goldenberg ◽  
D. N. Harris ◽  
M. L. Ogletree
Keyword(s):  
Ex Vivo ◽  
Shape Change ◽  
Concentration Effect ◽  
Antithrombotic Activity ◽  
Thromboxane Receptor ◽  
Effect Curve ◽  
Thromboxane Receptors ◽  
The Right

SQ 30741 was characterized as a competitive antagonist of thromboxane receptor-mediated platelet activation in vitro that does not inhibit the activity of enzymes involved in prostaglandin, prostacyclin, and thromboxane biosynthesis. The threshold intravenous dose for antithrombotic activity was measured in anesthetized monkeys as the minimum amount of SQ 30741 required to inhibit thrombotic cyclic blood flow reductions in stenotic renal arteries. Platelet responsiveness was measured ex vivo before and during inhibition of thrombosis by the shape-change response to a thromboxane mimetic, U 46619. The threshold antithrombotic SQ 30741 dose (0.32 +/- 0.04 mg/kg; n = 5) was accompanied by an 8.5 +/- 1.1-fold shift to the right of the U 46619 concentration-effect curve, implying antagonism of 87 +/- 3% of platelet thromboxane receptors. The antithrombotic activity of SQ 30741 persisted for 109 +/- 10 min and was not reversed by indomethacin. However, in two out of seven monkeys SQ 30741 (7 mg/kg iv) did not interrupt the cyclical flow reductions. Vehicle treatment did not impede thrombosis and caused a 1.4 +/- 0.3-fold shift of the U 46619 concentration-effect curve (n = 4). In separate monkeys, SQ 30741 (0.33 mg/kg iv) produced identical dose ratios (8.6 +/- 0.7, n = 8) for inhibition of U 46619-induced mesenteric vasoconstriction. Thus the threshold antithrombotic dose of SQ 30741 caused the same magnitude of antagonism of platelet (ex vivo) and vascular (in vivo) thromboxane receptors.

Positive inotropic effect of the thromboxane analog U-46619 on guinea pig left atrium: mediation by specific receptors and association with increased phosphoinositide turnover

1989 ◽  
Vol 67 (8) ◽  
pp. 943-949 ◽  
Author(s):  
Ichiro Sakuma ◽  
Steven S. Gross ◽  
Roberto Levi
Keyword(s):  
Guinea Pig ◽  
Left Atrium ◽  
Positive Inotropic Effect ◽  
Inositol Phosphates ◽  
Inotropic Effect ◽  
Lipoxygenase Inhibitors ◽  
Phosphoinositide Turnover ◽  
Thromboxane Receptor ◽  
Specific Receptors ◽  
Thromboxane Receptors

U-46619, a stable epoxymethano analog of thromboxane A2 elicited a direct positive inotropic effect on guinea pig left atrium paced at a constant rate (EC50 = 2.5 nM). This novel observation contrasts with previous reports of a decrease in myocardial contractility by thromboxane mimetic compounds in coronary-perfused preparations, an action recognized as secondary to vasoconstriction. The positive inotropic effect of U-46619 was competitively antagonized by the specific thromboxane receptor blocker L-655,240 (pA2 = 8.02; identical to that reported in smooth muscle), but was unaffected by blockers of α1-, β1-, and H1-receptors and by cyclooxygenase and lipoxygenase inhibitors. Increased tissue levels of inositol phosphates, but not cAMP, were associated with the positive inotropic action of U-46619, in analogy to the actions of α1- and H1-receptor agonists. However, the inotropic effect of U-46619 and the concomitant increase in phosphoinositide breakdown were both selectively antagonized by L-655,240. Thus, U-46619 acts on specific thromboxane receptors in guinea pig left atrium and elicits a positive inotropic effect that probably results from an increase in phosphoinositide metabolism.Key words: thromboxane analog U-46619, positive inotropic effect, guinea pig left atrium, phosphoinositide turnover, compound L-655-240.

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