Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor

Article abstract of DOI:10.1021/jm00012a012

The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives as specific and competetive inhibitors of platelet activating factor (PAF), are described.Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-<2-<(3,4,5-trimethoxybenzoyl)oxy>ethyl>-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-<2-<<4-(hexyloxy)-3,5-dimethoxybenzoyl>oxy>ethyl>-N,N,N-trimethylammonium iodide (3, pK_b 5.43).Furth er SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-<4-(4-methylthiazol-5-yl)butyl>benzene (38) (pK_b 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.