197855-64-4Relevant articles and documents
Synthesis and biological activity of a series of potent fluoromethyl ketone inhibitors of recombinant human calpain I
Chatterjee, Sankar,Ator, Mark A.,Bozyczko-Coyne, Donna,Josef, Kurt,Wells, Gregory,Tripathy, Rabindranath,Iqbal, Mohamed,Bihovsky, Ron,Senadhi, Shobha E.,Mallya, Satish,O'Kane, Teresa M.,McKenna, Beth Ann,Siman, Robert,Mallamo, John P.
, p. 3820 - 3828 (1997)
Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of stroke. In this paper, we report on a series of potent dipeptide fluoromethyl ketone inhibitors of recombinant human calpain I (rh calpain I). SAR studies revealed that while calpain I tolerates a variety of hydrophobic groups at the P1 site, Leu at P2 is preferred. However, the nature of the N-terminal capping group has a significant effect on the inhibitory activity of this series of compounds. Compound 4e [(1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl-Leu-D,L-Phe- CH2F], having a tetrahydroisoquinoline containing urea as the N-terminal capping group, is the most potent dipeptide fluoromethyl ketone inhibitor of calpain 1 (with a second-order rate constant for inactivation of 276 000 M- 1 s-1) yet reported; tripeptide 4k (Cbz-Leu-Leu-D,L-Phe-CH2F) is equipotent. A number of compounds presented in this study displayed excellent selectivity for calpain I over cathepsins B and L, two related cysteine proteases. Compounds which exhibited good inhibitory activity in the assay against isolated rh calpain I also inhibited intracellular calpain I in a human cell line. Thus, in an intact cell assay, compounds 4e and 4k inhibited calpain I with IC50 values of 0.2 and 0.1 μM, respectively. Finally, we also disclose the first example of fluorination of a dipeptide enol silyl ether to generate the corresponding dipeptide fluoromethyl ketone.
