9,11-epoxy-9-homoprosta-5-enoic acid analogues as thromboxane A2 receptor antagonists.
A novel bicyclic prostaglandin analogue, (1S)-[1 alpha, 2 alpha(Z),3 alpha(1E,3S*,4R*),4 alpha]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (4), was found to be a potent and selective thromboxane A2 (TxA2) receptor antagonist. Alcohol 4 was the only member in a series of allylic alcohols which did not display direct contractile activity in the rat stomach strip model. Alcohol 4 was effective in the inhibition of (a) arachidonic acid induced platelet aggregation of human platelet-rich plasma (I50 = 0.65 +/- 0.1 microM); (b) 11,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (pA2 = 8.0 +/- 0.2) or rat aorta (pA2 = 8.1 +/- 0.2); and (c) arachidonic acid induced bronchoconstriction in the anesthetized guinea pig (1 mg/kg iv). A radioiodinated analogue of 4 bound in a specific and saturable manner to human platelet membranes with a Kd = 2.3 +/- 0.9 nM. Modification of the alpha-chain, in an attempt to minimize in vivo metabolism, resulted in TxA2 receptor antagonists of reduced in vitro potency.
Das
J
J
Department of Chemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Hall
S E
SE
Nakane
M
M
Haslanger
M F
MF
Reid
J A
JA
Garber
D
D
Truc
V C
VC
Harris
D N
DN
Hedberg
A
A
Ogletree
M L
ML
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005343:Fibrinolytic Agents; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors; D051381:Rats; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D015656:Respiratory Mechanics / Q000187:drug effects; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; C050448:SQ 28668