| Autor: |
Wang Y; Procter & Gamble Pharmaceuticals, Inc., 8700 Mason-Montgomery Road, Mason, OH 45040, USA., 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 |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2007 Feb 01; Vol. 15 (3), pp. 1311-22. Date of Electronic Publication: 2006 Nov 10. |
| DOI: |
10.1016/j.bmc.2006.11.011 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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