| Abstract
| - Calpain I, an intracellular cysteine protease, has been implicatedin the neurodegenerationfollowing an episode of stroke. In this paper, we report on aseries of potent dipeptidefluoromethyl ketone inhibitors of recombinant human calpain I (rhcalpain I). SAR studiesrevealed that while calpain I tolerates a variety of hydrophobic groupsat the P1 site, Leu at P2is preferred. However, the nature of the N-terminal capping grouphas a significant effect onthe inhibitory activity of this series of compounds. Compound4e [(1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl-Leu-d,l-Phe-CH2F],having a tetrahydroisoquinoline containing urea as theN-terminal capping group, is the most potent dipeptidefluoromethyl ketone inhibitor of calpainI (with a second-order rate constant for inactivation of 276 000M-1 s-1) yetreported; tripeptide4k(Cbz-Leu-Leu-d,l-Phe-CH2F) isequipotent. A number of compounds presented in thisstudydisplayed excellent selectivity for calpain I over cathepsins B and L,two related cysteineproteases. Compounds which exhibited good inhibitory activity inthe assay against isolatedrh calpain I also inhibited intracellular calpain I in a human cellline. Thus, in an intact cellassay, compounds 4e and 4k inhibited calpain Iwith IC50 values of 0.2 and 0.1 μM,respectively.Finally, we also disclose the first example of fluorination of adipeptide enol silyl ether togenerate the corresponding dipeptide fluoromethyl ketone.
|
