Akaji et al. discovered a series of SARS‐CoV‐1 Mpro inhibitors derived from its natural peptide substrate. Initially, they designed a pentapeptide (Ac‐Ser‐Val‐Leu‐N(CH3)2Gln‐CHO, 44) with Mpro inhibitory activity of 37 µM. 147  SAR studies of 44 led to inhibitor containing P1‐imidazole with improved potency (45; IC50, 5.7 µM). Further systematic structural modifications, primarily concentrating on P1‐, P2‐, and P4‐moieties, driven by X‐ray structure‐based analyses of the Mpro‐inhibitor complex, led to the identification of inhibitor 46 with remarkable inhibitory activity (IC50, 98 nM). The crystal structure of Mpro with 46 revealed significant binding interactions in the active site. The P1‐imidazole nitrogen atom created a hydrogen bond with the histidine residue's imidazole nitrogen, and the P2‐cyclohexyl moiety fitted well into the S2‐subsite. This compound was characterized as a competitive inhibitor without covalent bond formation.