7-OXABICYCLO[2.2.1]HEPTYL CARBOXYLIC-ACIDS AS THROMBOXANE-A2 ANTAGONISTS - AZA OMEGA-CHAIN ANALOGS

A novel bicyclic prostaglandin analogue, [lS-[la,2a(Z),3a,4a]]-7-[3-[[[[(l-Oxoheptyl)amino]acetyl]amino]-methyI]-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 w-chain ally lie 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-rich plasma (I50 = 0.18 ± 0.006 uM), (b) ll,9-epoxymethano-PGH2induced platelet aggregation of human platelet-rich plasma (I50 = 0.24 um), (c)ll,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (Kb = 3.0 ± 0.3 nM) or rat aorta (Kb- 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]-[lS-[la,2a(Z),3a,4a)]-7-[3-[[2-[(Phenyl-amino)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 Kd = 49.6 ±1.4 nM. © 1990, American Chemical Society. All rights reserved.