7-Oxabicyclo[2.2.1]heptyl carboxylic acids as thromboxane A2 antagonists: aza omega-chain analogues.
A novel bicyclic prostaglandin analogue, [1S-[1 alpha, 2 alpha (Z), 3 alpha, 4 alpha]]-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 omega-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-rich plasma (I50 = 0.18 +/- 0.006 microM), (b) 11,9-epoxymethano-PGH2 induced platelet aggregation of human platelet-rich plasma (I50 = 0.24 microM), (c) 11,9-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]-[1S- (1 alpha, 2 alpha (Z), 3 alpha, 4 alpha)]-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.
Nakane
M
M
Department of Chemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Reid
J A
JA
Han
W C
WC
Das
J
J
Truc
V C
VC
Haslanger
M F
MF
Garber
D
D
Harris
D N
DN
Hedberg
A
A
Ogletree
M L
ML
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D001372:Aza Compounds; D013928:Thromboxane A2