Dual-Acting Thromboxane Receptor Antagonist/Synthase Inhibitors: Synthesis and Biological Properties of [2-Substituted-4-(3-pyridyl)-1,3-dioxan-5-yl]alkenoic Acids

• Published in: Journal of medicinal chemistry 1995-02, Vol.38 (4), p.686-694
• Main Authors: Faull, Alan W, Brewster, Andrew G, Brown, George R, Smithers, Michael J, Jackson, Ruth
• Format: Article
• Language: English
• Subjects: Animals; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Cardiovascular system; Cells, Cultured; Dioxanes - chemical synthesis; Dioxanes - pharmacology; Dogs; Drug Design; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - metabolism; Humans; Medical sciences; Pharmacology. Drug treatments; Rats; Receptors, Thromboxane - antagonists & inhibitors; Thromboxane-A Synthase - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00004a014

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.