The synthesis and evaluation of peptidyl aspartyl aldehydes as inhibitors of ice

The tetrapeptide aldehyde Ac-Tyr-Val-Ala-AspH ( 1, L-709,049) has been reported to be a potent reversible inhibitor of Interleukin-1β Converting Enzyme (ICE). We have prepared a series of analogs of 1, in order to explore the active sige of ICE. The effects of truncation, methylation of the amide ni...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1994-10, Vol.4 (19), p.2359-2364
Main Authors: Mullican, Michael D., Lauffer, David J., Gillespie, Roger J., Matharu, Saroop S., Kay, David, Porritt, Geoffrey M., Evans, Phillip L., Golec, Julian M.C., Murcko, Mark A., Luong, Yu-Ping, Raybuck, Scott A., Livingston, David J.
Format: Article
Language:English
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Summary:The tetrapeptide aldehyde Ac-Tyr-Val-Ala-AspH ( 1, L-709,049) has been reported to be a potent reversible inhibitor of Interleukin-1β Converting Enzyme (ICE). We have prepared a series of analogs of 1, in order to explore the active sige of ICE. The effects of truncation, methylation of the amide nitrogens and modification of the aldehyde group of 1 are presented. The synthesis and SAR of L-709,049 ( 1) to explore the ICE active site is described. Removal of P4 or modification of the aldehyde results in significant loss of activity. N-methylation of the P 1 or P 3 amide nitrogens results in complete loss of activity, while N-methylation at P 2 or P 4 is tolerated.
ISSN:0960-894X
1464-3405
DOI:10.1016/0960-894X(94)85040-2