THROMBOXANE MODULATING AGENTS .3. 1H-IMIDAZOL-1-YLALKYL-SUBSTITUTED AND 3-PYRIDINYLALKYL-SUBSTITUTED 3-[2-[(ARYLSULFONYL)AMINO]ETHYL]BENZENEPROPANOIC ACID-DERIVATIVES AS DUAL THROMBOXANE SYNTHASE INHIBITOR THROMBOXANE RECEPTOR ANTAGONISTS/

The design of a series of dual thromboxane synthase inhibitor/thrombox ane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]be nzenepropanoic acid thromboxane receptor antagonist template is descri bed. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinylmet hyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with th romboxane synthase inhibitory activity comparable with that of dazmegr el (7). In addition, 3-pyridinylalkyl substituents also make a signifi cant contribution to thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting thro mboxane synthase inhibition and thromboxane receptor blockade as measu red by inhibition of U46619-induced platelet aggregation ex vivo.