Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2.
A series of chemically stable TXA2/PGH2 analogues modeled after the structure of the natural products was prepared in search of useful inhibitors of TXA2/PGH2-mediated pathophysiology. Each of the 16 isomers implied in structure 1 was prepared in chiral form and evaluated for activity in vitro in platelets and smooth muscle. Depending on relative side chain and carbinol stereochemistry, TXA2/PGH2 agonist and antagonist and, surprisingly, PGD2/PGI2 agonist activities were observed. The enantiomers possessing the alpha heterocycle shown in 1 were generally more potent than their mirror-image isomers.
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006801:Humans; D007536:Isomerism; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D011449:Prostaglandin Endoperoxides / Q000037:antagonists & inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014961:X-Ray Diffraction
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D044262:Prostaglandin H2; D013928:Thromboxane A2; C032408:SQ 26536; D013930:Thromboxane-A Synthase