Lactone and Cyclic Ether Analogues of Platelet-Activating Factor : Synthesis and Biological Activities

Abstract

Six-membered lactone and tetrahydropyran analogues of platelet-activating factor (PAF), 4-11, and related antagonistic derivatives 41-46 were synthesized. None of the δ-lactones 4-7 showed PAF-like activities, while the corresponding cyclic ethers 8, 9 and 11 were slightly active. Some of the cyclic antagonists showed more potent inhibitory activities than the open chain antagonist CV-3988 against platelet aggregation (rabbit platelet-rich plasma, IC₅₀) and hypotension (rat, DI₅₀) induced by C₁₆-PAF : e.g. dl-3-{6-[O-(trans-3-heptadeclcarbamoyloxytetrahydropyran-2-yl)methyl]phosphonoxy}hexylthiazolium (inner salt)(4ld)(IC₅₀5.5×10^-7M, ID₅₀0.046mg/kg, i.v.);dl-3-{5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2-yl)methyl]phosphonoxy}pentylthiazolium (inner salt) (43c) (IC₅₀5.7×10^-7M, ID₅₀0.076mg/kg, i.v.).