VS-based discovery of novel 1,5-disubstituted tetrazoles as MDM2 antagonists. >60 compounds were synthesized using a 2-step MCR chemistry. FP-monitored SAR analysis allowed for the fast optimization up to low nM potency. Compound 2.27 inhibited the MDM2/p53 interaction with a Ki of 20 nM. The affinity and the rough binding mode were also confirmed using 2D NMR.