Abstract
The synthesis and pharmacological evaluation of 5 (L-738, 167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be > 33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by > 85% 24 h after the oral administration of 5 to dogs at 100 micrograms/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
MeSH terms
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Adenosine Diphosphate / pharmacology
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Animals
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Azepines / chemical synthesis*
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Azepines / metabolism
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Azepines / pharmacology
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Collagen / pharmacology
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Dogs
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Fibrinogen / metabolism
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / chemistry
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Fibronectins / metabolism
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Humans
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Molecular Structure
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Platelet Aggregation Inhibitors / chemical synthesis
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Platelet Aggregation Inhibitors / pharmacology
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Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
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Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / metabolism
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Sulfonamides / pharmacology
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Vitronectin / metabolism
Substances
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Azepines
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Fibrinolytic Agents
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Fibronectins
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L 738167
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Platelet Aggregation Inhibitors
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Platelet Glycoprotein GPIIb-IIIa Complex
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Sulfonamides
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Vitronectin
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Adenosine Diphosphate
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Fibrinogen
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Collagen