Selective inhibitory actions of sodium-p-benzyl-4-[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl] phenyl phosphonate (N-0161) and indomethacin on the biosynthesis of prostaglandins and thromboxanes from arachidonic acid.
1 Sodium p-benzyl-4-[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164) selectively inhibited the formation of thromboxane-A(2) from prostaglandin endoperoxides by human platelet microsomes in a dose-dependent manner (IC(50) 2.2 x 10(-5) M or 11.6 mug/ml).2 N-0164 was approximately 15 to 20 times as potent as indomethacin as an inhibitor of thromboxane-A(2) formation. In contrast, indomethacin was 20 times as potent as N-0164 as an inhibitor of prostaglandin endoperoxide formation from arachidonic acid (IC(50) 2.6 x 10(-5) M or 9.4 mug/ml).3 Spiral strips of dog coronary arteries relaxed in the presence of prostaglandin endoperoxides and were contracted by prostaglandin E(2) and thromboxane-A(2) and were therefore used to distinguish between prostaglandins and their intermediate precursors, the endoperoxides.4 Neither indomethacin nor N-0164 (both 50 mug/ml) significantly inhibited the formation of prostaglandin-like activity from the endoperoxides following incubation with indomethacin-pretreated rabbit kidney medulla microsomes.5 It is not known whether this action of N-0164 is related to its ability to antagonize certain actions of prostaglandins (and related compounds) or whether N-0164 can penetrate the cell membrane to inhibit thromboxane formation in the intact cell.6 Selective inhibition of thromboxane formation by drugs such as N-0164 may be useful both clinically and as a pharmacological tool to elucidate the patho-physiological roles of the thromboxanes.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001158:Arteries / Q000187:drug effects; D001681:Biological Assay; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D003864:Depression, Chemical; D004285:Dogs; D005260:Female; D006801:Humans; D006880:Hydroxy Acids / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007679:Kidney Medulla / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010545:Peroxides / Q000096:biosynthesis; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000096:biosynthesis; D011714:Pyrans / Q000096:biosynthesis*; D011817:Rabbits; D012669:Seminal Vesicles / Q000378:metabolism / Q000648:ultrastructure; D012756:Sheep
D001095:Arachidonic Acids; D006880:Hydroxy Acids; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010545:Peroxides; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D011458:Prostaglandins E; D011714:Pyrans; C012641:N 0164; D007213:Indomethacin