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

Abstract

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.