7-Oxabicycloheptyl Carboxylic Acids as Thromboxane A2 Antagonists: Aza ω-Chain Analogues

Article abstract of DOI:10.1021/jm00171a021

A novel bicyclic prostaglandin analogue, <1S-<1α,2α(Z),3α,4α>>-7-<3-<<<<(1-Oxoheptyl)amino>acetyl>amino>methyl>-7-oxabicyclo<2.2.1>hept-2-yl>-5-heptenoic acid ((-)-7) was found to be a potent and selective thromboxane A₂ (TxA₂) receptor antagonist.Unlike the related series of ω-chain allylic alcohols, amide 7 and its congeners were uniformly free of direct contractile activity in vitro (bovine coronary) and in vivo (anesthetized guinea pig).Amide 7 was effective in the inhibition of (a) arachidonic acid induced platelet aggregation of human platelet-richplasma (I50 = 0.18 +/- 0.006 μM), (b) 11,9-epoxymethano-PGH2 induced platelet aggregation of human platelet-rich plasma (I50 = 0.24 μM), (c) 11,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (K_b = 3.0 +/- 0.3 nM) or rat aorta (K_b = 8.8 +/- 1.1 nM), and (d) arachidonic acid induced bronchoconstriction in the anesthetized guinea pig (0.1-1.0 mg/kg iv).Amide 7 inhibited the binding of <5,6-3H2>-<1S-<1α,2α(Z),3α,4α>>-7-<3-<<2-<(Phenylamino)carbonyl>hydrazino>methyl>-7-oxabicyclo<2.2.1>hept-2-yl>-5-heptenoic acid to human platelet membranes in a specific and saturable manner with a K_d = 49.6 +/- 1.4 nM.