SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF NOVEL BENZOPYRAN-CONTAINING PLATELET-ACTIVATING-FACTOR ANTAGONISTS

A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little affect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and 0-substituents resulted in the analogues 25-27 which exhibited K(i) values ranging between 131 and 167 nM in a [H-3]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.