Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2(TxA2)antagonists. Semicarbazone .omega.-chains

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 > meta >> 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-mu-M) and U-46,619 (10-mu-M) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20-mu-M) induced aggregation was observed at > 1000-mu-M. Receptor binding studies with [H-3]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a K(d) 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 postanoid-like series of TxA2 antagonists with the maintainance of potent antagonistic activity.