Peptide Based Interleukin-1β Converting Enzyme (ICE) Inhibitors : Synthesis, Structure Activity Relationships and Crystallographic Study of the ICE-inhibitor Complex

Abstract

Based on the X-ray structure of the complex of Ac-Tyr-Val-Ala-Asp-H (L-709049) and interleukin-1β converting enzyme (ICE), we synthesized compounds which were derived from 2-NapCO-Val-Pro-Asp-CH₂OPh (1) to obtain a potent inhibitor in the cell assay. Among these compounds, (3S)-N-methanesulfonyl-3-[[1-[N-(2-naphthoyl)-L-valyl]-L-prolyl]amino]-4-oxobutanamide (27c) showed high potency not only in the enzyme assay but also cell assay with IC₅₀ values of 38 nM and 0.23 μM, respectively. Compound 27c, with a c log P value of 1.76, had more hydrophilic character compared with 1. Compound 27c also dose dependently inhibited LPS-primed ATP-induced IL-1β release in mice. The crystal structure of the complex of compound 27c and ICE revealed that compound 27c had further interactions with ICE in the naphthoyl group at the P4 position and in the methyl group of the methanesulfonamidecarbonyl group at the P1 position, compared with L-709049. To our knowledge, compound 27c is the first example that shows a strong inhibitory activity without the carboxyl group at the P1 position.