Synthesis and pharmacological evaluation of 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptane derivatives.
1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-Epoxy-3- (3-cyclohexyl-3-hydroxy-3-methyl-1-propenyl)-7-oxabicyclo[2.2.1]-hept-2- yl]-5-heptenoic acid (31) and [1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-epoxy-3-[3-hydroxy-5-(p-hydroxyphenyl)-1- pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (37) were found to be selective TxA2 antagonists at the platelet and pulmonary thromboxane receptors. An efficient stereospecific synthesis of these compounds and a series of structural analogues is described. Compounds 31 and 37 both inhibited the bronchoconstriction induced by arachidonic acid in the anesthetized guinea pig.
Das
J
J
Department of Chemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Vu
T
T
Harris
D N
DN
Ogletree
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ML
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006536:Heptanes / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D004852:Epoxy Compounds; D005229:Fatty Acids, Monounsaturated; D006536:Heptanes; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C055761:7-(5,6-epoxy-3-(3-hydroxy-5-(4-hydroxyphenyl)-1-pentenyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid; C055760:7-(5,6-epoxy-3-(3-cyclohexyl-3-hydroxy-3-methyl-1-propenyl)-7-oxabicyclo(2.2.1)-hept-2-yl)-5-heptenoic acid; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate