Analogues of platelet activating factor. 6. Mono- and bis-aryl phosphate antagonists of platelet activating factor.

A series of aryl phosphoglyceride (3, 19-61) and bis-aryl phosphate (67-135) antagonists of platelet activating factor (PAF) were prepared. A group of four bifunctional phosphorus reagents (5a-c and 7) were developed that allowed the preparation of these aryl phosphates in which the position of aromatic substitution can be varied. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. Selected compounds were also evaluated for their ability to displace [3H]PAF from its receptor on rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in both the mouse and rabbit, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Compound 105 (CL 184005) has been selected to undergo further development as a potential therapeutic agent for the treatment of septic shock in man.