New analogues of 13-hydroxyocatdecadienoic acid and 12-hydroxyeicosatetraenoic acid block human blood platelet aggregation and cyclooxygenase-1 activity (original) (raw)
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European Journal of Pharmacology, 1984
Structural requirements for preventing the aspirin-and the arachidonate-induced inactivation of platelet cyclo-oxygenase: additional evidence for distinct enzymatic sites, European J. Pharmacol. 97 (1984) 197-208. 2-Hydroxybenzoic acid (salicylic acid) prevents the inhibition by aspirin (ASA) of platelet aggregation and of the generation of thromboxane A 2 from arachidonic acid (AA). We studied the ability of 2-hydroxybenzoic acid analogues to block ASA and to prevent the platelet desensitization due to a first exposure to AA. Inactivation was prevented when exposure to AA was done in the presence of reversible inhibitors of cyclo-oxygenase. Phenol, methyl salicylate and L8027 were thus strong inhibitors of AA-induced platelet activation and desensitization. The minimal structural requirement for inhibition of thromboxane A 2 generation from AA was a phenol group as benzoic acid was fully inactive. 2-Hydroxybenzoic acid, and to some extent 2,6-dihydroxybenzoic acid were effective against ASA, the most active substances being methyl salicylate and L8027. The minimal structural requirement for blocking ASA was that 2-hydroxybenzoic acid, 2-methoxybenzoic acid should be devoid of activity, which highlights the fact that the hydroxyl group must be available. Our work favours the hypothesis that non-steroidal anti-inflammatory drugs react with two sites of cyclo-oxygenase, which were named the supplementary and the catalytic sites. The interaction of 2-hydroxybenzoic acid and of its analogues with the supplementary site is necessary but not sufficient for the efficacy of these compounds as cyclo-oxygenase inhibitors. The intensity of interaction with the supplementary site and the modifications of the catalytic site determine the potency of these compounds as cyclo-oxygenase inhibitors. For preventing ASA inactivation, an interaction with the supplementary sites is always necessary, but furthermore an appropriate group, preferentially in the position ortho to the hydroxyl, is needed.
Archiv der Pharmazie, 2018
A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a-x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3Tfibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18...
Bioorganic & Medicinal Chemistry, 2003
A series of anilides and phenyl esters of piperidine-3-carboxylic acid (nipecotic acid) were synthesized and tested for the ability to inhibit aggregation of human platelet rich-plasma triggered by adenosine 5 0 -diphosphate (ADP) and adrenaline. As a rule, amides were about two times more active than the corresponding esters, and derivatives bearing substituents at the para position of the phenyl ring were significantly more active than the meta-substituted ones. Among the tested compounds, 4-hexyloxyanilide of nipecotic acid (18a) was found to be the most active one, its IC 50 value being close to that of the most active bis-3-carbamoylpiperidines reported in literature (ca. 40 mM) and aspirin (ca. 60 mM) in ADP-and adrenaline-induced aggregation, respectively. Compared with the isomeric 4-hexyloxyanilides of piperidine-2-carboxylic (pipecolinic) and piperidine-4-carboxylic (isonipecotic) acids, compound 18a showed higher activity, and a Hansch-type quantitative structure-activity relationship (QSAR) study highlighted lipophilicity and increase in electron density of the phenyl ring as the properties which mainly increase the antiplatelet activity (r 2 =0.74, q 2 =0.64). The interaction of nipecotoyl anilides with phosphatidylinositol, a major component of the inner layer of the platelet membranes, was investigated by means of flexible docking calculation methods to give an account of a key event underlying their biological action. #
Journal of inflammation (London, England), 2014
Aspirin is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is also a commonly used anti-platelet drug, which inhibits the formation of the platelet activator, thromboxane A2 (TxA2) via inhibition of cyclooxygenase-1 (COX-1). However, the presence of a patient subset that fails to respond to aspirin despite reduced TxA2 concentrations suggests that the effect of aspirin might be more complex than exclusive COX-1 inhibition. In this study we evaluated the impact of in vivo oral administration of a standard anti-platelet dose (75 mg) of aspirin in healthy volunteers on the acute impact of in vitro collagen-mediated platelet aggregation and generation of platelet-derived TxA2 and the 12-lipoxygenase (LOX) metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The eicosanoids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Low-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of ...
Platelet aggregation is the process by which platelets adhere to each other at sites of vascular injury. This process has long been recognized as critical for hemostatic plug formation and thrombosis. Until relatively recently, platelet aggregation was considered a straightforward process involving the non-covalent bridging of integrin αIIbβ3 receptors on the platelet surface by the dimeric adhesive protein fibrinogen. Naturally occurring triterpenes are endowed with a broad range of useful pharmacological properties. In our search for new and potent ethnopharmaceuticals, oleanolic acid (OA) (1), ursolic acid (UA) (2) betulinic acid (BA) (3), and maslinic acid (MA) (4) isolated from Syzygium aromaticum, Eucalyptus grandis, Callistemon viminalis, and Syzygium aromaticum, respectively, were evaluated in vitro for anti-platelet aggregation activity on thrombin, adenosine diphosphate (ADP), and epinephrine-induced rat platelet aggregation. The triterpenes exhibited a dose dependent inhibitory activity on platelet aggregation induced by the three platelet agonists. The compounds exhibited more potency mostly at the highest concentration (10.0 mg/ml) except for UA (2) on thrombin-induced platelet aggregation. The percentage inhibitory activity of UA (2) on throbine-induced platelet aggregation was found to decrease with increase in concentration (86.8±1.23, 53.0±0.43, 46.2±0.23) 1-10.0 mg/ml, this invariably suggests an optimal concentration (≤ 1.0 mg/ml). The IC50s of the compounds are remarkably better than that of heparin (IC50 of 2.80mg/ml). The highest activity by OA (1) (IC50 of 0.84 mg/ml) and mixture of BA/OA (IC50 of 2.61 mg/ml) was observed on thrombin-induced platelet aggregation. BA/OA (IC50 of 2.57 mg/ml) also showed a significant platelet aggregation inhibitory activity on epinephrine-induced platelet aggregation. These preliminary findings show that these pentacyclic triterpenoic acids possess pharmacological activity and could be potential templates for development of new anti-platelet agents
journal of applied pharmaceutical science, 2022
Several well-known synthetic drugs, such as aspirin, elinogrel, and beraprost, and natural drugs, such as eptifibatide and vorapaxar, as platelet aggregation inhibitors are widely used in clinical medicine today. The purpose of this review is a comparative pharmacological analysis of the biological activity of these drugs with natural sulfur-containing hydrocarbons isolated from bacteria, plants, and mineral oils. According to the quantitative structure-activity relationship estimates, these naturally occurring sulfur-containing hydrocarbons are more likely to exhibit antiplatelet properties than those currently used in clinical medicine.
European Journal of Pharmaceutical Sciences, 2001
Two isomeric aspirin derivatives of isosorbide-5-mononitrate (ISMN) were prepared and evaluated as potential mutual prodrugs of aspirin and nitric oxide. The hydrolysis of both compounds was studied in pH 7.4 phosphate buffer solution, buffered a-chymotrypsin solution and 10% buffered rabbit plasma. The benzodioxin-4-one derivative was hydrolysed to salicylic acid and ISMN acetate in buffer solution (t 32.1 h), 10% buffered rabbit plasma (t 25.7 min) and a-chymotrypsin (t 86.6 min). The carboxylic acid ester derivative 1 / 2 1 / 2 1 / 2 ISMNA was hydrolysed via the salicylate ester in buffer solution (t 48.5 h) but was rapidly and almost exclusively hydrolysed to 1 / 2 aspirin and ISMN in plasma solution (t 2.8 min). The hydrolysis appeared to be enzyme mediated as it was suppressed by 1 / 2 co-incubation with eserine. ISMNA was evaluated for its ability to inhibit platelet aggregation in rabbit PRP in response to the following agonists: arachidonic acid (AA) (100 mM), ADP (1.2 mM), phorbol ester (0.5 mM), platelet activating factor (PAF) (5 nM) and the thromboxane mimic U46619 (1.5 mM). ISMNA suppressed platelet response to AA at 1 mM whereas 10 mM aspirin showed no inhibitory effects.
Journal of Pharmacy and Pharmacology, 2004
In an effort to develop potent antiplatelet agents with anti-inflammatory action, a novel series of anti-inflammatory chalcones was screened to evaluate their antiplatelet effects. Structure-activity relationships and mode of action were investigated and characterized. The antiplatelet effects of the chalcones on washed rabbit platelets and human platelet-rich plasma were evaluated. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the chalcone derivatives. Collagen-induced platelet aggregation was potently inhibited by all the chalcone derivatives at 300 M, except for compound 4 at 100 M. Compounds 6, 7 and 9 significantly inhibited the aggregation of washed rabbit platelets induced by platelet-activating factor at 300 M. Of the compounds tested in human platelet-rich plasma, compounds 2, 8 and 9 showed significant inhibition of secondary aggregation induced by adrenaline. It is concluded that the antiplatelet effect of 2, 8 and 9 is mainly owing to an inhibitory effect on thromboxane formation. The inhibitory effect of 6, 7 and 9 on platelet aggregation induced by platelet-activating factor could be owing to a calcium antagonizing effect or inhibition of intracellular calcium mobilization.
New chemical structures of hypolipidemic and antiplatelet activity
Pure and Applied Chemistry, 2001
Elevated lipid level is supposed to be one of the main risk factors of atherosclerosis and subsequent cardiovascular disease (and is connected to mortality). Therefore, lipid lowering is one of the major targets in cardiovascular disease treatment and prevention. Also, blood platelets play a pivotal role in the development of atherosclerosis and fatal thrombus formation in the course of coronary heart disease. Therefore, there is a great necessity to acquire drugs inhibiting platelet aggregation and clot generation. The present paper reviews new chemical structures in development for the treatment and prevention of hyperlipidemia, atherosclerosis, and subsequent cardiovascular disease. The authors' recent results are also reported regarding synthesis of a new group of a-asarone analogs. These compounds were identified as an original class of agents exhibiting hypolipidemic and antiplatelet (mice, rats) activities. Although the mechanism of the compounds' pharmacological acti...