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.
Faull
A W
AW
ZENECA Pharmaceuticals, VIMS Department, Macclesfield, Cheshire, U.K.
Brewster
A G
AG
Brown
G R
GR
Smithers
M J
MJ
Jackson
R
R
D000818:Animals; D002478:Cells, Cultured; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D004146:Dioxanes; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase