Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2 antagonists. Semicarbazone omega-chains

J Med Chem. 1991 Sep;34(9):2882-91. doi: 10.1021/jm00113a030.


A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[[[(phenylamino) carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl] benzenepropanoic acid, was identified as a potent and long-acting TxA2 antagonist. In human platelet rich plasma SQ 35,091 inhibited arachidonic acid (800 microM) and U-46,619 (10 microM) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 microM) induced aggregation was observed at greater than 1000 microM. Receptor binding studies with [3H]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a Kd value of 1.0 +/- 0.1 nM in human platelet membranes. In vivo SQ 35,091 (0.2 mg/kg po) showed extended protection (T50 = 16 h) from U-46,619 (2 mg/kg iv) induced death in mice. These compounds have for the first time demonstrated that a metabolically stable interphenylene alpha-sidechain can be introduced into a prostanoid-like series of TxA2 antagonists with the maintainance of potent antagonistic activity.

MeSH terms

  • Adenosine Diphosphate / antagonists & inhibitors
  • Animals
  • Arachidonic Acid
  • Arachidonic Acids / antagonists & inhibitors
  • Blood Platelets / drug effects
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic*
  • Cell Membrane / drug effects
  • Fatty Acids, Unsaturated
  • Humans
  • Hydrazines / pharmacology
  • Magnetic Resonance Spectroscopy
  • Mice
  • Semicarbazones / chemistry
  • Semicarbazones / pharmacology*
  • Stereoisomerism
  • Thromboxane A2 / antagonists & inhibitors*


  • Arachidonic Acids
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Fatty Acids, Unsaturated
  • Hydrazines
  • Semicarbazones
  • SQ 35091
  • Arachidonic Acid
  • Thromboxane A2
  • Adenosine Diphosphate
  • SQ 29548