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

Article abstract of 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 be highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho > meta >> para. SQ 35,091 (25), [1S-(1α,2α,3α,4α)]-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 μM) and U-46,619 (10 μM) induced aggregation with I₅₀ values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 μM) induced aggregation was observed at >1000 μM. Receptor binding studies with [³H]-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 α-sidechain can be introduced into a prostanoid-like series of TxA₂ antagonists with the maintenance of potent antagonistic activity.