DUAL-ACTING THROMBOXANE RECEPTOR ANTAGONIST SYNTHASE INHIBITORS - SYNTHESIS AND BIOLOGICAL PROPERTIES OF SUBSTITUTED-4-(3-PYRIDYL)-1,3-DIOXAN-5-YL]ALKENOIC ACIDS

The design, synthesis, and pharmacology of a new class of compounds po ssessing both thromboxane receptor antagonist and thromboxane synthase inhibitory properties are described. Replacement of the phenol group of the known thromboxane antagonist series R)-4-(2-hydroxyphenyl)-1,3- dioxan-5-yl]hex-4-enoic acid by a 3-pyridyl group led to a series of c ompounds, 5, which were potent thromboxane synthase inhibitors and wea k thromboxane antagonists. Further modifications at the dioxane C2 pos ition led to compounds, 7, which were potent dual-acting agents. In th e case of compound 7w, the dual activity was shown to reside almost ex clusively in the (-)-enantiomer, 7x. Following oral dosing to rats and dogs, 7x (3 mg/kg) displayed significant dual activity over a period of at least 8 h.