FROM PEPTIDE TO NONPEPTIDE .2. THE DE-NOVO DESIGN OF POTENT, NON-PEPTIDAL INHIBITORS OF PLATELET-AGGREGATION BASED ON A BENZODIAZEPINEDIONESCAFFOLD

Earlier studies of peptides containing the arginine-glycine-aspartic a cid (RGD) sequence led to the development of a structural model descri bing the three-dimensional presentation required for RGD-mediated inhi bition of glycoprotein IIbIIIa/fibrinogen binding. We describe here th e use of that structural model to design a rigid, non-peptidal lead se ries that reproduces the topography of the peptide backbone using a be nzodiazepinedione scaffold. This scaffold is used to synthesize novel molecules which are highly potent inhibitors of platelet aggregation a nd which possess improved bioavailability. The importance of shape as a design criterion is demonstrated by constructing molecules that pres ent alternative topographies; these molecules are shown to be signific antly less potent.