A NOVEL-APPROACH TO DUAL-ACTING THROMBOXANE RECEPTOR ANTAGONIST SYNTHASE INHIBITORS BASED ON THE LINK OF 1,3-DIOXANE-THROMBOXANE RECEPTOR ANTAGONISTS AND 1,3-DIOXANE-THROMBOXANE SYNTHASE INHIBITORS

A new class of dual-acting racemic thromboxane receptor antagonist/thr omboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel(11) (separately) to thromboxane receptor antagonists ( TXRA) from the 1,3-dioxane series, such as ICI 192605 (10). Dual activ ity was observed in vitro with inhibition of human microsomal thrombox ane synthase in the range IC50 = 0.01-1.0 mu M and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation i n the range pA(2) = 5.5-7.0. The in vitro results also showed that ver y large groups could be tolerated at the selected substitution positio ns of the TXRA and TXSI components. Oral activity was observed in ex v ivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, -2-yl]ben zyl]oxy]phenyl]-7-(3-pyridyl)hept-6-enoic acid (110) was both an antag onist (pA(2) = 6.7) and a synthase inhibitor (IC50 = 0.02 mu M). On or al dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA act ivity [concentration ratio >64 (rat, 3 h) and >59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thrombo xane synthase at the respective time points in these experiments was 8 1 +/- 4.4% (rat) and 69 +/- 4.8% (dog).