Abstract
The design of a series of dual thromboxane synthase inhibitor/thromboxane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid thromboxane receptor antagonist template is described. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinyl-methyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with thromboxane synthase inhibitory activity comparable with that of dazmegrel (7). In addition, 3-pyridinylalkyl substituents also make a significant contribution to thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting thromboxane synthase inhibition and thromboxane receptor blockade as measured by inhibition of U46619-induced platelet aggregation ex vivo.
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Administration, Oral
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Animals
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Dogs
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Microsomes / enzymology
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Molecular Structure
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Muscle Contraction / drug effects
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Phenylpropionates / chemical synthesis*
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Phenylpropionates / pharmacology
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / chemical synthesis*
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacology
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Rats
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Receptors, Thromboxane / antagonists & inhibitors*
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Structure-Activity Relationship
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Thromboxane-A Synthase / antagonists & inhibitors*
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Thromboxanes / agonists
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Thromboxanes / blood
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Thromboxanes / metabolism
Substances
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Enzyme Inhibitors
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Imidazoles
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Phenylpropionates
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Platelet Aggregation Inhibitors
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Pyridines
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Receptors, Thromboxane
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Thromboxanes
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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Thromboxane-A Synthase