piperidines and thrombin-receptor-peptide-(42-55)

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active GP IIb/IIIa antagonist after oral administration. This clinical investigation evaluated whether coadministration of oral aspirin or intravenous heparin would alter the pharmacokinetics or pharmacodynamics of oral sibrafiban. Twenty-four adult subjects received two of the following four combinations: sibrafiban alone, sibrafiban with ASA, sibrafiban with heparin, and sibrafiban with ASA and heparin, separated by a 2-week washout period. Concentration profiles of active drug in citrate and EDTA plasma were unchanged with coadministration of ASA or heparin. No pharmacodynamic interaction was seen with coadministration of heparin. Inhibition of platelet aggregation increased 4% to 55%, and Ivy bleeding time increased 58% to 87% with coadministration of sibrafiban and ASA. The combined pharmacodynamic effect of sibrafiban and ASA may indicate a potentially greater therapeutic effect but an increased risk of bleeding when these drugs are used in combination.

Topics: Adenosine Diphosphate; Administration, Oral; Adult; Anticoagulants; Area Under Curve; Aspirin; Bleeding Time; Cross-Over Studies; Drug Interactions; Female; Heparin; Humans; Male; Middle Aged; Oximes; Partial Thromboplastin Time; Peptide Fragments; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prodrugs; Prothrombin Time; Receptors, Thrombin

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.

Topics: Azepines; Blood Platelets; Drug Design; Humans; In Vitro Techniques; Indicators and Reagents; Isoxazoles; Peptide Fragments; Piperidines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptor, PAR-1; Receptors, Thrombin; Structure-Activity Relationship; Thrombin

The effect of thrombin receptor activation on monocyte conformation was evaluated using the human monocyte cell line, THP-1, and the thrombin mimetic peptide, Trap-14. Treatment of THP-1 cells with Trap-14 induced rapid rounding of ameboid cells adherent to fibronectin-coated slides, whereas cell rounding was abrogated in the presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine or the endothelin B receptor antagonist, BQ-788. Endothelin-1 (ET-1) levels in the culture supernatant increased markedly within minutes of Trap-14 exposure with a concomitant loss in cellular ET-1 immunoreactivity. Importantly, loss of ET-1 immunoreactivity was blocked by pretreatment with the vesicle translocation inhibitor, nocodazole. Trap-14 potently induced the release of NO from THP-1 cells, whereas NO release was ablated by preincubation with BQ-788. These data demonstrate that thrombin receptor activation may inhibit cellular spreading as a result of autocrine ET-1 release and subsequent endothelin B receptor-dependent NO production, and suggest that initial exposure of inflammatory cells to thrombin may limit cellular activation and recruitment.

Topics: Cell Adhesion; Cell Size; Endothelin Receptor Antagonists; Endothelin-1; Humans; Leukemia, Monocytic, Acute; Monocytes; Nitric Oxide; Nocodazole; Oligopeptides; Peptide Fragments; Piperidines; Receptor, Endothelin B; Receptors, Endothelin; Receptors, Thrombin; Thrombin; Tumor Cells, Cultured