Analogues of platelet activating factor. 8. Antagonists of PAF containing an aromatic ring linked to a pyridinium...

A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards.