SELECTIVE INHIBITORY ACTIONS OF SODIUM‐p‐BENZYL‐4‐[1‐OXO‐2‐(4‐CHLOROBENZYL)‐3‐PHENYL PROPYL] PHENYL PHOSPHONATE (N‐O164) 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-A₂ from prostaglandin endoperoxides by human platelet microsomes in a dose-dependent manner (IC₅₀ 2.2 × 10⁻⁵ m or 11.6 μg/ml). 2 N-0164 was approximately 15 to 20 times as potent as indomethacin as an inhibitor of thromboxane-A₂ formation. In contrast, indomethacin was 20 times as potent as N-0164 as an inhibitor of prostaglandin endoperoxide formation from arachidonic acid (IC₅₀ 2.6 × 10⁻⁵ m or 9.4 μg/ml). 3 Spiral strips of dog coronary arteries relaxed in the presence of prostaglandin endoperoxides and were contracted by prostaglandin E₂ and thromboxane-A₂ and were therefore used to distinguish between prostaglandins and their intermediate precursors, the endoperoxides. 4 Neither indomethacin nor N-0164 (both 50 μg/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.