AbstractFR900452, a natural product isolated from the culture broth ofStreptomyces phaeofaciens No. 7739, was found to inhibit PAF‐induced rabbit platelet aggregation with an IC50 of 3.7×10−7M. FR900452, 1‐methyl‐3‐[1‐[5‐methylthiomethyl‐6‐oxo‐3‐(2‐oxo‐3‐cyclopenten‐1‐ylidene)‐2‐piperazinyl]ethyl]‐2‐indoline, has an oxocylopentylidene group incorporated as a vinylogous amide in a diketopiperazine skeleton. This unique structure led us to synthesize diketopiperazine derivatives, 3‐arylalkyl‐6‐substituted‐piperazine‐2,5‐diones. their observed PAF inhibitory activity suggest that the D‐D configuration of diketopiperazine is an important factor for anti‐PAF activity and that the hydrophobic aromatic portion may play a specific role in the binding of the diketopiperazine to the PAF receptor.