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Synthesis and evaluation of unsaturated caprolactams as interleukin-1beta converting enzyme (ICE) inhibitors.

Abstract：

:Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Wang Y,O'Neil SV,Wos JA,Oppong KA,Laufersweiler MC,Soper DL,Ellis CD,Baize MW,Fancher AN,Lu W,Suchanek MK,Wang RL,Schwecke WP,Cruze CA,Buchalova M,Belkin M,De B,Demuth TP Jr

doi

10.1016/j.bmc.2006.11.011

subject

Has Abstract

pub_date

2007-02-01 00:00:00

pages

1311-22

issue

3

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(06)00942-4

journal_volume

15

pub_type

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