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PubMed1990

[Synthesis of 4,5-diarylthiazole derivatives as blood platelet aggregation inhibitors].

A number of 2-substituted 4,5-diphenylthiazoles were synthesized by the nucleophilic substitution of 2-methylsulfonyl-4,5-diphenylthiazole with various sodium alkoxides, amines, and carbanions of active methylene compounds. 2-Methylsulfonyl-4,5-diphenylthiazole was obtained by the potassium permanganate oxidation of 2-methylthio-4,5-diphenylthiazole in the presence of a phase-transfer catalyst. 2-Ethoxy-4,5-bis(4-methoxyphenyl) thiazole was prepared in a similar manner. 2-Ethynyl-4,5-diphenylthiazoles were synthesized by the palladium catalyst cross-coupling reaction of 2-iodo-4,5-diphenylthiazole with monosubstituted acetylenes. These compounds were tested for inhibitory activity against blood platelet aggregation in vitro. Among them, 2-alkoxy-, and 2-(4-methylpiperazin-1-yl)-4,5-diphenylthiazole were found to have potent inhibitory activity.

Benzene Derivatives↗
PubMed1981

Cyclic guanidines. 14. Imidazo[1,2-a]thienopyrimidin-2-one derivatives as blood platelet aggregation inhibitors.

A series of novel 1,2,3,5-tetrahydroimidazo[1,2-a]thieno[2,3-d]-, -[3,2,-d]-, and -[3,4-d]pyrimidin-2-one derivatives has been prepared and tested for the activity of inhibiting platelet aggregation in rats in vitro and ex vivo. These compounds were synthesized through the following reactions: sodium borohydride reduction of 2,4-dichlorothienopyrimidines, followed by ethoxycarbonylmethylation and successive amination. Most of the compounds were found to be potent inhibitors of blood and platelet aggregation. Structure-activity relationships have indicated the essential contribution of the lactam structure and lipophilic substituents on the thiophene ring to the effective interaction of the compounds with a receptor site on the platelet. Among the compounds studied, 1,2,3,5,6,7,8,9-octahydro-[1]benzothieno[2,3-d]imidazo[1,2-a]pyrimidin-2-one (9m) exhibited the most favorable activity.

Animals↗
PubMed2001

[Spontaneous intraspinal epidural hematoma secondary to use of platelet aggregation inhibitors].

HISTORY AND ADMISSION FINDINGS: A 64-year-old woman previously in good health experienced an acute onset of severe neck pain and weakness of the left arm that had developed within minutes. Neurological examination revealed paresis of the left arm. There was a previous history of cardiovascular disease and she had been treated with 100 mg of aspirin per day. INVESTIGATIONS: MRI revealed a left posterolateral intraspinal mass extending from C3 to C7. The hemostatic evaluation showed no abnormalities (platelet count, prothrombin time, partial thromboplastin time). TREATMENT AND COURSE: A laminectomy with evacuation of the epidural hematoma was performed. The postoperative course was uneventful, with complete disappearance of the neurological deficit. CONCLUSION: We report a rare condition of spontaneous spinal epidural hematoma that was associated with aspirin intake. A short time interval from onset of symptoms to diagnosis (MRI) and surgery is crucial for the outcome.

Angina Pectoris↗
PubMed1992

Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.

The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.

Dinoprostone↗
PubMed1996

2-Pyridylarylhydrazone derivatives, a new class of platelet aggregation inhibitors.

A series of 2-pyridylarylhydrazone derivatives was synthesized and compared with a previously reported pyrazole series, i.e., 4-acylpyrazolylarylhydrazone and 5-pyrazolylarylhydrazone, which present antiplatelet aggregation activity. The structures of these pyridylarylhydrazone derivatives were designed on the basis of the known bioisosteric relationship of the heteroaromatic ring. The antiplatelet aggregation activity was measured in vitro on citrated platelet-rich rabbit plasma in which aggregation was induced with 5 microM ADP, 5 micrograms/ml collagen and 200 microM arachidonic acid. Eighteen compounds belonging to the pyridine series were tested at 1 mM concentration and none inhibited ADP-induced rabbit platelet aggregation. 2-(2-Formylfurane)pyridylhydrazone exhibited a highly potent inhibitory activity on arachidonic acid-induced aggregation, with an IC50 of 0.35 microM. These results suggest that the hydrazone unit and the 2-furyl moiety of the arylhydrazone framework are important pharmacophores for antiplatelet activity.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1997

[Anticoagulants and platelet aggregation inhibitors in urology].

Anticoagulants are widely used in the prevention of thromboembolic disease (particularly during the postoperative period) and in the curative treatment of deep vein thromboses. Two classes of anticoagulants are currently available: heparins (standard heparin, low molecular weight heparin) and coumarin anticoagulants. The choice of anticoagulant must take into account the clinical context (preventive or curative treatment), as well as the pharmacological and pharmacokinetic properties of the anticoagulant. This treatment requires laboratory monitoring adopted to the anticoagulant selected.

Anticoagulants↗
PubMed2000

Purification, cloning, expression, and mechanism of action of a novel platelet aggregation inhibitor from the salivary gland of the blood-sucking bug, Rhodnius prolixus.

Rhodnius prolixus aggregation inhibitor 1 (RPAI-1), a 19-kDa protein isolated from the salivary gland of R. prolixus, was purified by strong cation exchange and reverse-phase high performance liquid chromatographies. Based on 49 amino-terminal amino acid sequences of RPAI-1, primers were produced to generate probes to screen an R. prolixus salivary gland cDNA library. A phage containing the full-length clone of RPAI-1 codes for a mature protein of 155 amino acids. RPAI-1 shows sequence homology to triabin and pallidipin, lipocalins from Triatoma pallidipennis. The cDNA sequence was cloned in Pet17B Escherichia coli expression vector, producing an active peptide. RPAI-1 inhibits human platelet-rich plasma aggregation triggered by low concentrations of ADP, collagen, arachidonic acid, thromboxane A(2) mimetics (U46619), and very low doses of thrombin and convulxin. Here we show that ADP is the target of RPAI-1 since (i) RPAI-1 inhibits ADP-dependent large aggregation formation and secretion triggered by U46619, without affecting Ca(2+) increase and shape change; (ii) ADP restored the inhibition of U46619-induced platelet aggregation by RPAI-1, (iii) PGE(1)-induced increase of cAMP (which is antagonized by U46619 in an ADP-dependent manner) was restored by RPAI-1, (iv) RPAI-1 inhibits low concentrations of ADP-mediated responses of indomethacin-treated platelets, and (v) RPAI-1 binds to ADP, as assessed by large zone chromatography. RPAI-1 affects neither integrin alpha(2)beta(1)- nor glycoprotein VI-mediated platelet responses. We conclude that RPAI-1 is the first lipocalin described that inhibits platelet aggregation by a novel mechanism, binding to ADP.

Adenosine Diphosphate↗
PubMed1999

Determination of the impurity profile of ethyl-2-(4-[(5R)-3[4-(methoxycarboxamidoiminomethyl)-phenyl]-2- oxo-5-oxazolidinylmethyl]-1-piperazinyl) acetate, citrate, a highly active platelet aggregation inhibitor, by liquid chromatography-mass spectrometry.

Ethyl-2-(4-[(5R)-3-[4-(methoxycarboxamidoiminomethyl)-phenyl] -2-oxo-5-oxazolidinylmethyl]-1-piperazinyl) acetate, a glycoprotein IIb/IIIa antagonist, is a drug substance of the oxazolidinone type from Merck's research to be developed for the chronic oral treatment of thrombotic disorders. For the separation of the byproducts in the bulk drug substance, a reversed-phase HPLC gradient separation was developed. The eluent consisting of a nonvolatile phosphate buffer system had to be changed to a volatile acetate buffer system in order to perform on-line LC-MS coupling. With a triple quadrupole system it was possible to characterize most of the unknown byproducts occuring during synthesis and during scale-up to kg amounts of the bulk drug substance.

Chromatography, Liquid↗
PubMed2002

[Platelet aggregation inhibitor in general practice. Every 3rd infarct prevented--reinfarction rate cut in half].

Depending on their mode of action, pharmaceuticals with an antithrombocytic effect are divided into five groups. In the doctor's office, acetylsalicylic acid (ASA) and the thienopyridines, such a ticlopidine and clopidogrel predominate. Acetylsalicylic acid should be considered for primary prevention in patients over 50 with a marked cardiovascular risk profile. In the secondary prophylaxis of myocardial infarction, life-long ASA treatment continues to be the treatment of choice. As an alternative, however, clopidogrel may be applied. A combination of acetylsalicylic acid and clopidogrel is recommended for patients who have been implanted with a stent. In patients with acute coronary syndrome, this regimen is superior to monotherapy with acetylsalicylic acid. In comparison with ticlopidine, clopidogrel has a more rapid onset of action, and has fewer side effects. In patients with an acute coronary syndrome and an elevated risk glycoprotein IIb/IIIa antagonists have proved highly effective.

Aspirin↗
PubMed1995

[Synthesis of new platelet aggregation inhibitors substituted with pyridylisoxazoles and their 4,5-dihydroanalogs].

A number of substituted pyridylisoxazoles and their 4,5-dihydro analogs were synthesized by 1,3-dipolar cycloaddition of substituted nitrile oxides to either alkenes or alkynes. The synthesized compounds inhibit arachidonic acid-induced aggregation of human thrombocytes at concentrations of 10(-6) to 10(-3) M. Due to low toxicity, these compounds can be regarded as potential antithrombosis medicines.

Arachidonic Acid↗
PubMed2002

[Secondary and primary prevention of coronary heart disease: platelet aggregation inhibitors and anticoagulants].

This review presents the results of primary and secondary prevention of coronary heart disease (CHD) with antiplatelet drugs and anticoagulants; therapeutic recommendations are derived. According to the results of the trials and due to its low price aspirin (ASS) can be still considered as the drug of choice. Its protective action has been documented for secondary prevention in patients with previous myocardial infarction, coronary angioplasty (PCI), unstable and stable angina, but not in patients with coronary artery bypass surgery, heart failure as well as in primary prevention. The doses recommended are 75-325 mg/d. If ASS is not tolerated clopidogrel is an alternative, but an expensive one. Anticoagulation for primary prevention of CHD may be considered in high risk patients, who do not tolerate ASS (alternative: clopidogrel). In secondary prevention anticoagulation is only recommended for special conditions, such as ASS intolerance (alternative: clopidogrel), ventricular aneurysm, ventricular thrombus, severe heart failure and/or atrial fibrillation.

Anticoagulants↗
PubMed1993

Platelet aggregation inhibitors in neurology.

This literature review reports on secondary prevention of ischaemic stroke. The aim of secondary prevention is to protect patients who belong to a risk group from the occurrence of brain infarction. Symptomatic patients with a demonstrated carotid artery stenosis of 70% and more will most probably benefit from carotid endarterectomy if performed by a skilled surgeon in the absence of contraindications. Oral anticoagulant drugs play a minor role in the medical prevention of brain infarction. Antiplatelet drugs, however, have been in use for almost two decades and (meta-)analysis of clinical trials points to acetylsalicylic acid as a drug with a modest but certain contribution of about 15% in the endpoint reduction, even at lower dosages. The addition of dipyridamole to classic acetylsalicylic acid dose appears to increase the endpoint reduction to 30%. Neither dipyridamole nor sulfinpyrazone as monotherapy have been demonstrated to be efficacious in the secondary prevention of ischaemic stroke. Ticlopidine seems a promising alternative for acetylsalicylic acid in those patients who suffer adverse effects from acetylsalicylic acid. Ticlopidine itself, however, has a number of side-effects that limit its application. New clinical trials are under way in order to improve the efficacy of drug treatment in the secondary prevention of brain infarction.

Brain Ischemia↗
PubMed1995

Isolation and identification of seven metabolites of a water-soluble platelet aggregation inhibitor in rat urine.

1. Seven metabolites of 7-piperidino-1,2,3,4,5-tetrahydroimidazo[2,1- b]quinazolin-2-one dihydrochloride monohydrate (DN-9693) were isolated from rat urine by extraction with Amberlite XAD-2 and purification by silica gel and Sephadex LH-20 open-column chromatography and preparative high-performance liquid chromatography (hplc). The structure assignment of the metabolites was performed by field desorption mass spectrometry and 200-MHz Fourier transform nmr spectroscopic analysis and comparison with authentic standards when available. 2. DN-9693 underwent metabolism mainly at the piperidine ring to give the 4-hydroxypiperidine derivative (III) and 2-hydroxy-piperidine derivative, which is further metabolized to lactam (II) or delta-aminovaleric acid (V). The acyl side chain of V was shortened by beta-oxidation to form the 3-aminopropionic acid derivative (VII). V and/or VII underwent oxidative dealkylation to give the 7-amino derivative, which was conjugated with acetic acid to form the 7-acetylamino derivative (IV). DN-9693 also underwent hydrolysis of its lactam moiety to give VI. 3. The urinary excretion of III, V and VII was determined by liquid chromatography/electrochemistry (LC/EC) and V proved to be the major metabolite in rat urine. 4. A procedure is also presented for the identification of DN-9693 metabolites using LC/EC.

Animals↗
PubMed1996

Animal pharmacokinetics and interspecies scaling from animals to man of lamifiban, a new platelet aggregation inhibitor.

Relating pharmacokinetic information obtained in animal species to man (interspecies scaling) can play an important role in enabling understanding of the differences and similarities between species, and helping to predict the kinetic profile of a new compound in man. Interspecies scaling techniques have been applied to lamifiban (Ro 44-9883), a new selective and potent nonpeptidic inhibitor of human glycoprotein IIb-IIIa intended for use in clinical treatment of, for example, acute coronary syndrome. The pharmacokinetic profile of lamifiban in man was predicted from animal data (in rats, dogs and cynomolgus monkeys) by using allometric scaling and concentration-time transformations. These extrapolations for lamifiban were performed prospectively, to help design the first pharmacokinetic studies in man. The approach based on equivalent time was preferred for our prospective predictions, in view of the high values found for the allometric exponents. Using allometric scaling, clearance (CL), half-life (t1/2) and volume of distribution (Vd) were overestimated by approximately two- to fourfold. Compared with allometric scaling, the transformation based on equivalent time improved the prediction for all human pharmacokinetic parameters. For t1/2 and CL, the observed values for man were within the range predicted from the various animal species. Of the individual animal species, the cynomolgus monkey gave the most reliable predictions of these two parameters, as well as accurately predicting the Vd value.

Acetates↗
PubMed1992

Structural domains in venom proteins: evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venoms are derived by proteolysis from a common precursor.

A comparison of the structures of a precursor of trigramin (a disintegrin), metalloproteinases, disintegrins and related proteins, suggests the existence of common precursors for metalloproteinases and disintegrins. The proposed common precursor and related proteins have four distinct domains (A-D). Domain B contains the metal binding site and the catalytic Glu residue, which comprise the active site of metalloproteinases. Domain C contains the Arg-Gly-Asp sequence and hence the ability to inhibit the activity of integrins. Domains A and D are unique and their biochemical or biological activity is unknown. The proposed precursor can be proteolytically cleaved at several interdomain sites, releasing the disintegrins and metalloproteinases. A survey of more than 100 venom metalloproteinases and disintegrins strongly supports the existence of precursor proteins and their structural domains. This is also upheld by the co-occurrence occurrence of metalloproteinases and disintegrins in the venoms of several genera of crotalid and viperid snakes. The likelihood of intradomain disulfide bridges, and accessibility of all interdomain cleavage sites also supports our contention. The susceptibility of the cleavage sites appears to be determined by nearby disulfide bridges and glycosylation. Recognition of the proposed structural domains of venom proteinases should help clarify the structure-function relationships of several related proteins, and influence the synthesis of recombinant disintegrins, metalloproteinases and related polypeptides.

Amino Acid Sequence↗
PubMed2003

The influence of tick behavior, biotope and host specificity on concerted evolution of the platelet aggregation inhibitor savignygrin, from the soft tick Ornithodoros savignyi.

Ticks are obligate blood-feeding parasites that secrete anti-hemostatic components during feeding to enable control of the hemostatic system of the host. Complex interactions at the tick-host interface are an indication of the important role that the host played during tick evolution. The question is to what extent interaction with the host and the environment influences tick evolution. Previously, two isoforms (97% sequence identity) of savignygrin, an alphaIIbbeta3 antagonist, have been described. The presence of both isoforms within 20 random individuals confirmed that these isoforms must be recent gene duplicates. Analysis of the sequence differences between the isoforms shows a Kn/Ks ratio of 1, which indicates neutral selection for the isoforms. However, the biased localization of differences within the 3' end of the genes suggests that concerted evolution acts on the isoforms. Calculation of the divergence date between the isoforms (1.6-5.2 MYA) also indicates purifying selection, as ample time had passed after duplication, for inactivation of one gene copy. We conclude that concerted evolution has functioned to maintain a high copy number of the savignygrins in order for Ornithodoros savignyi to parasitize a wide host range. This contrasts with O. moubata that expresses the savignygrin homolog, disagregin, as a single copy at lower concentration levels and correlates with the confined habitat and consequently narrow host range of O. moubata. Recent "domestication" of O. savignyi due to animal husbandry practices could however, have reduced the selection constraints acting to maintain the gene copies as evidenced by the structural instability of one of the isoforms. Our results suggest that environmental factors and host associations do play an important role in the evolution of anti-hemostatic components in ticks.

Alleles↗