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

Earlier studies of peptides containing the arginine-glycine-aspartic acid (RGD) sequence led to the development of a structural model describing the three-dimensional presentation required for RGD-mediated inhibition of glycoprotein IIbIIIa/fibrinogen binding. We describe here the use of that structural model to design a rigid, non-peptidal lead series that reproduces the topography of the peptide backbone using a benzodiazepinedione scaffold. This scaffold is used to synthesize novel molecules which are highly potent inhibitors of platelet aggregation and which possess improved bioavailability. The importance of shape as a design criterion is demonstrated by constructing molecules that present alternative topographies; these molecules are shown to be significantly less potent.