DEVELOPMENT OF A NOVEL SERIES OF TRIALKOXYARYL DERIVATIVES AS SPECIFIC AND COMPETITIVE ANTAGONISTS OF PLATELET-ACTIVATING-FACTOR

The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecu lar modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N- imethoxybenzoyl)oxy]ethyl]-N ,N,N-trimethylammonium iodide (1) from the Wellcome registry of compou nds and to the synthesis of the lead compound imethoxybenzoyl]oxy]ethy l]-N,N,N-trimethylammonium iodide (3, pK(b) 5.43). Further SAR conside rations directed the design to dimethoxy-5-[4-(4-methylthiazol-5-yl)bu tyl]benzene (38) (pK(b) 7.14), a novel, specific, and competitive inhi bitor of the PAF receptor in rabbit-washed platelets.