piperidines and lotrafiban

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vas

Topics: Animals; Benzodiazepines; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.. Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.. Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aspirin; Benzodiazepines; Cerebrovascular Disorders; Coronary Disease; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Proportional Hazards Models; Risk Assessment; Treatment Outcome

Our objective was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of lotrafiban, an oral glycoprotein IIb/IIIa inhibitor, in patients with a recent myocardial infarction, unstable angina, transient ischemic attack, or stroke.. A 12-week, double-blind, multi-center, placebo-controlled, parallel-group, phase II study of lotrafiban (the Anti-platelet Useful Dose Study) was conducted in patients. Lotrafiban or placebo was administered as a twice daily oral dose at four dose levels (5-100 mg) for 12 weeks with daily doses of aspirin (300-325 mg). The pharmacokinetics of lotrafiban were characterized with the use of a population approach and were described by a two-compartment model with first order absorption and first order elimination. The pharmacodynamic data, ex vivo platelet aggregation, were described with the use of a direct effect inhibitory sigmoidal model with a baseline. The relationship between the severity of bleeding episodes and predicted steady-state lotrafiban exposure was characterized by logistic regression.. Pharmacokinetic analysis showed that increasing age and decreasing creatinine clearance resulted in increased exposure to lotrafiban. The concentration-effect relationship was steep, with near complete inhibition of platelet aggregation at lotrafiban concentrations in excess of 20 ng/mL. Logistic regression showed that at exposures that exceeded approximately 835 ng. h/mL, the severity of adverse bleeding events increased considerably; this suggested that dosing recommendations should be generated to minimize the likelihood of patients having an area under the plasma concentration-time curve from 0 to 24 hours in excess of this value.. Patients whose age exceeded 65 years or whose creatinine clearance was less than 60 mL/min should be given a lower dose of lotrafiban than younger patients with good renal function.

Topics: Adult; Age Factors; Aged; Benzodiazepines; Creatinine; Demography; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Diseases; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Sex Factors

Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.. Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.. The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

Topics: Administration, Oral; Adolescent; Arterial Occlusive Diseases; Benzodiazepines; Double-Blind Method; Drug Evaluation; Female; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Myocardial Ischemia; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Research Design; Secondary Prevention; Stroke

Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease.. Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%.. -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Topics: Administration, Oral; Aged; Benzodiazepines; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombocytopenia; Treatment Outcome

Thromboembolic events (TEE) underwrite key causes of death in developed countries. While advanced imaging technologies such as computed tomography scans serve to diagnose blood clots during acute cardiovascular events, no such technology is available in routine primary care for TEE risk assessment. Here, we describe an imaging platform technology based on bioengineered fluorescent nanodiamond particles (F-NDPs) functionalized with bitistatin (Bit), a disintegrin that specifically binds to the α

Topics: Animals; Benzodiazepines; Blood Platelets; Fibrinogen; Humans; Nanodiamonds; Peptides; Piperidines; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Rats, Inbred F344; Receptors, Fibrinogen; Snake Venoms; Thrombin; Thrombosis

The integrin alpha(IIb)beta(3) is the major mediator of platelet aggregation and has, therefore, become an important target of antithrombotic therapy. Antagonists of alpha(IIb)beta(3), for example abciximab, tirofiban and eptifibatide, are used in the treatment of acute coronary syndromes. However, in addition to effective blockade of the integrin, binding of can induce conformational changes in the integrin and can also induce integrin clustering. This class effect of RGD-ligand mimetics might, therefore, underlie paradoxical platelet activation and thrombosis previously reported.. To examine the components of signaling pathways and functional responses in platelets that may underlie this phenomenon of paradoxical platelet activation.. We assessed the effect of lotrafiban, and other alpha(IIb)beta(3) antagonists including the clinically used drug tirofiban, on tyrosine phosphorylation of key signaling proteins in platelets by immunoblotting and also platelet functional outputs such as cytosolic calcium responses, phosphatidylserine exposure (pro-coagulant activity) and dense granule release.. In all cases, no effect of alpha(IIb)beta(3) antagonists were observed on their own, but these integrin antagonists did lead to a marked potentiation of glycoprotein VI (GPVI)-associated FcR gamma-chain phosphorylation, activation of Src family kinases and Syk kinase. This correlated with increased dense granule secretion, cytosolic calcium response and exposure of phosphatidylserine on the platelet surface. P2Y(12) antagonism abolished the potentiated phosphatidylserine exposure and dense granule secretion but not the cytosolic calcium response.. These data provide a mechanism for enhancement of platelet activity by alpha(IIb)beta(3) inhibitors, but also reveal a potentially important signaling pathway operating from the integrin to GPVI signaling.

Topics: Benzodiazepines; Biomimetics; Blood Coagulation; Blood Platelets; Calcium Signaling; Enzyme Activation; Humans; Immunoglobulin gamma-Chains; Intracellular Signaling Peptides and Proteins; Ligands; Oligopeptides; Phosphatidylserines; Phosphorylation; Piperidines; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Protein Conformation; Protein-Tyrosine Kinases; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Secretory Vesicles; src-Family Kinases; Syk Kinase; Time Factors; Tirofiban; Tyrosine

Migration of megakaryocytes (MKs) from the proliferative osteoblastic niche to the capillary-rich vascular niche is essential for proplatelet formation and platelet release. In this study, we explore the role of surface glycoprotein receptors and signaling proteins in regulating MK migration and platelet recovery after immune-induced thrombocytopenia. We show that spreading and migration of mouse primary bone marrow-derived MKs on a fibronectin matrix are abolished by the Src family kinases inhibitor PP1, the Syk kinase inhibitor R406 and the integrin alphaIIbbeta3 antagonist lotrafiban. We also demonstrate that these responses are inhibited in primary phospholipase C gamma2 (PLCgamma2)-deficient MKs. Conversely, MK spreading and migration were unaltered in the absence of the collagen receptor, the glycoprotein VI-FcRgamma-chain complex. We previously reported a correlation between a defect in MK migration and platelet recovery in the absence of platelet endothelial cell adhesion molecule-1 and the tyrosine phosphatase CD148. This correlation also holds for mice deficient in PLCgamma2. This study identifies a model in which integrin signaling via Src family kinases and Syk kinase to PLCgamma2 is required for MK spreading, migration, and platelet formation.

Topics: Animals; Benzodiazepines; Blood Platelets; Cell Movement; Cell Shape; Cells, Cultured; Intracellular Signaling Peptides and Proteins; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxazines; Phospholipase C gamma; Phosphorylation; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Proto-Oncogene Proteins pp60(c-src); Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Pyridines; Pyrimidines; Signal Transduction; Syk Kinase; Thrombopoiesis

von Willebrand factor (VWF) plays a critical role in the process of hemostasis by mediating flow-dependent adhesion and spreading of platelets on exposed extracellular matrix proteins following vascular injury. To accomplish this, VWF binds to two distinct platelet receptors: glycoprotein (GP)Ib-IX-V and integrin alpha(IIb)beta3.. To evaluate the ability of GPIb and alpha(IIb)beta3 to mediate platelet adhesion and lamellipodia formation on immobilized VWF in the presence of the biochemical modulators, ristocetin and botrocetin.. In the presence of botrocetin and inhibitors of adenosine diphosphate (ADP) and thromboxane A2 (TxA2), VWF is able to support formation of lamellipodia through a GPIb-dependent mechanism that is independent of alpha(IIb)beta3 and PI3-kinase. Lamellipodia formation under these conditions is incomplete. In marked contrast, in the presence of ristocetin, VWF stimulates formation of fully spread lamellipodia through a pathway that is dependent upon alpha(IIb)beta3 and PI3-kinase. Furthermore, alpha(IIb)beta3 also supports platelet spreading on VWF alone, but only in the absence of inhibitors of ADP and TxA2. The localization of filamentous actin and the Arp2/3 complex in platelets on VWF in the presence of botrocetin and ristocetin are distinct, yielding disparate lamellipodium kinetic signatures. Interestingly, botrocetin significantly enhances platelet adhesion to VWF under flow in whole blood in an alpha(IIb)beta3-independent manner, while ristocetin augments washed platelet adhesion and spreading to VWF under flow in an alpha(IIb)beta3-dependent manner.. These observations demonstrate that VWF is able to induce lamellipodia formation through distinct receptors, and has important consequences for investigation of the role of VWF-GPIb interactions in the context of platelet regulation.

Topics: Actin Cytoskeleton; Animals; Benzodiazepines; Blood Platelets; Crotalid Venoms; Cytoskeleton; Humans; In Vitro Techniques; Mice; Mice, Knockout; Neuropeptides; Phosphatidylinositol 3-Kinases; Piperidines; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Pseudopodia; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; RAC2 GTP-Binding Protein; Ristocetin; Signal Transduction; src-Family Kinases; von Willebrand Factor

Collagen and collagen-related peptide (CRP) activate platelets by interacting with glycoprotein (GP)VI. In addition, collagen binds to integrin alpha2beta1 and possibly to other receptors. In this study, we have compared the role of integrins alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Inhibitors of ADP and thromboxane A2 (TxA2) substantially attenuated collagen-induced platelet aggregation and dense granule release, whereas CRP-induced responses were only partially inhibited. Under these conditions, a proportion of platelets adhered to the collagen fibres resulting in dense granule release and alphaIIbbeta3 activation. This adhesion was substantially mediated by alpha2beta1. The alphaIIbbeta3 antagonist lotrafiban potentiated CRP-induced dense granule release, suggesting that alphaIIbbeta3 outside-in signalling may attenuate GPVI signals. By contrast, lotrafiban inhibited collagen-induced dense granule release. These results emphasise the differential roles of alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Further, they show that although ADP and TxA2 greatly facilitate collagen-induced platelet activation, collagen can induce full activation of those platelets to which it binds in the absence of these mediators, via a mechanism that is dependent on adhesion to alpha2beta1.

Topics: Adenosine Diphosphate; Benzodiazepines; Carrier Proteins; Collagen; Cytoplasmic Granules; Dual Specificity Phosphatase 2; Humans; Integrin alpha2beta1; P-Selectin; Peptides; Piperidines; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Protein Phosphatase 2; Protein Tyrosine Phosphatases; Thromboxane A2

The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.

Topics: Administration, Oral; Benzodiazepines; Coronary Disease; Humans; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Stroke

Several oral glycoprotein (GP) IIb/IIIa antagonists, Sibrafiban, Orbofiban and Lotrafiban, have been studied in large phase III trials; each has failed to provide efficacy and has been associated with increased mortality. Roxifiban has pharmacokinetic and pharmacodynamic properties believed to be more favorable than the earlier oral agents. Here, we revisit the controversial hypothesis of platelet activation liabilities of GP IIb/IIIa antagonists. The effects of site occupancy by four fibans (Roxifiban, Sibrafiban, Orbofiban and Lotrafiban) on platelet activation was assessed using P-selectin expression, fibrinogen binding and microaggregate formation. All four fibans inhibited ADP and TRAP-stimulated fibrinogen binding and microaggregate formation in a concentration-dependent manner, whereas P-selectin expression was relatively unaltered. To more vigorously test for activation liabilities, the effects of transition from peak to trough receptor occupancy upon platelet stimulation was analyzed. The high affinity of Roxifiban for resting platelets precluded reduction of site occupancy by dialysis or gel filtration. A method was developed that takes advantage of the rapid equilibrium of Roxifiban between platelets and soluble GPIIb/IIIa. The platelet occupancy is controlled by the ratio of platelet GPIIb/IIIa to soluble GPIIb/IIIa. This method allows in vitro investigation of peak/trough transitions on platelet activation. A decrease in site occupancy from peak to trough of Roxifiban or Sibrafiban did not result in increased activation of platelets. The loss of platelet-bound antagonist upon incubation with purified soluble GPIIb/IIIa returned fibrinogen binding/microaggregate formation to no drug levels. In conclusion, these studies do not provide evidence for an activation liability of GPIIb/IIIa antagonists in vitro.

Topics: Alanine; Amidines; Benzodiazepines; Blood Platelets; Humans; In Vitro Techniques; Isoxazoles; Oximes; P-Selectin; Piperidines; Platelet Adhesiveness; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Thrombosis

In patients with acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal myocardial infarction and repeat percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical thrombosis models. This report documents the preclinical data of Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.

Topics: Acute Disease; Animals; Benzodiazepines; Coronary Thrombosis; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Male; Piperidines; Platelet Aggregation

Topics: Administration, Oral; Benzodiazepines; Clinical Trials, Phase III as Topic; Hemorrhage; Humans; Myocardial Infarction; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Stroke; Treatment Outcome

Topics: Animals; Benzodiazepines; Caspase 3; Caspases; Cells, Cultured; Coumarins; Enzyme Activation; Fibrinolytic Agents; Heart; Myocardium; Oligopeptides; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Rats; Rats, Sprague-Dawley

[reaction: see text] The CuI-catalyzed coupling reaction of aryl halides with beta-amino acids or beta-amino esters is completed at 100 degrees C in 48 h, which indicates that the structure of the beta-amino acid has an accelerating effect for the Ullmann-type aryl amination reaction. This coupling reaction can be used to prepare enantiopure N-aryl beta-amino acids. An efficient synthetic route to SB214857, a potent GPIIb/IIIa receptor antagonist, is developed using this method.

Topics: Amino Acids; Benzodiazepines; Catalysis; Copper; Hydrocarbons, Halogenated; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Stereoisomerism