The synthesis of ketomethylene pseudopeptide analogues of dipeptide aldehyde inhibitors of calpain

The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cb z-Val-Ala-H have been prepared and the K-i values versus chicken gizzard sm ooth muscle calpain were determined. The ketomethylene isosteres were signi ficantly less potent than the corresponding dipeptide aldehydes, and this l oss in activity is attributed to the absence of a critical interaction betw een the P1-P2 amide bond and the peptide binding region of calpain. (C) 199 9 Elsevier Science Ltd. All rights reserved.