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.

Article Details

Citation

Copy to clipboard

Ackerley N, Brewster AG, Brown GR, Clarke DS, Foubister AJ, Griffin SJ, Hudson JA, Smithers MJ, Whittamore PR

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.

J Med Chem. 1995 May 12;38(10):1608-28.

PubMed ID

7752186 [ View in PubMed

]

Abstract

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dazoxiben	Thromboxane-A synthase	IC 50 (nM)	70	N/A	N/A	Details