Thromboxane Modulating Agents. 3. 1H-Imidazol-1-ylalkyl- and 3-Pyridinylalkyl-Substituted 3-[2-[(Arylsulfonyl)amino]ethyl]benzenepropanoic Acid Derivatives as Dual Thromboxane Synthase Inhibitor/Thromboxane Receptor Antagonists

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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-pyridinylmethyl), 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.

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