A novel approach to dual-acting thromboxane receptor antagonist/synthase inhibitors based on the link of 1,3-dioxane-thromboxane receptor antagonists and -thromboxane synthase inhibitors.

A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane 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 activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 microM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0. The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components. Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, (E)-7-[4-[[4-[(2SR,4SR,5RS)-5-[(Z)-5-carboxypent -2-enyl]-4-(2- hydroxyphenyl)-1,3-dioxan-2-yl]-benzyl]oxy]phenyl]-7-(3-pyridyl)he pt-6- enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 microM). On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity [concentration ratio > 64 (rat, 3 h) and > 59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4% (rat) and 69 +/- 4.8% (dog).

Dual-acting thromboxane receptor antagonist/synthase inhibitors: synthesis and biological properties of [2-substituted-4-(3-pyridyl)-1,3-dioxan-5-yl] alkenoic acids.

The design, synthesis, and pharmacology of a new class of compounds possessing both thromboxane receptor antagonist and thromboxane synthase inhibitory properties are described. Replacement of the phenol group of the known thromboxane antagonist series 4(Z)-6-[(4RS,5SR)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl] hex-4-enoic acid by a 3-pyridyl group led to a series of compounds, 5, which were potent thromboxane synthase inhibitors and weak thromboxane antagonists. Further modifications at the dioxane C2 position led to compounds, 7, which were potent dual-acting agents. In the case of compound 7w, the dual activity was shown to reside almost exclusively 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.

The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605.

The synthesis and summary pharmacology of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1, 3-dioxan-cis-5-yl) hexenoic acid (3) is reported. Compound 3 was competitive and selective with pA2 values of 8.0 +/- 0.1 (rabbit) and 8.4 +/- 0.05 (rat) on smooth muscle preparations and 8.16 +/- 0.01 on human platelets. In vivo activity of 3 was demonstrated in a Konzett Rossler guinea pig model at 0.01 mg/kg p.o.

(5Z)-7-(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoi c acid: a specific thromboxane A2 receptor antagonist.

(5Z)-7-(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (2) was found to be a specific, competitive thromboxane A2 receptor antagonist that acts at platelet, vascular, and pulmonary receptors. No antagonism was detected at receptors for prostacyclin, SRSA, norepinephrine, and serotonin. The synthesis of a series of analogues is described; activity at the thromboxane receptor was observed in cis-substituted compounds but not in their trans counterparts. Compound 2 inhibited the bronchoconstriction induced by a stable thromboxane mimetic in the anesthetized guinea pig.