A series of novel ketoamides incorporating all four 2,3-methanoleucine stereoisomers at the P2 position was synthesized. The compounds displayed a wide variation in Ki values for inhibition of calpain I depending on the configuration of the P2 methanoleucine residue. However, similar variation in cathepsin B inhibition was not observed suggesting that the S2 pocket of calpain I is more stereosensitive than that of cathepsin B.