Author/Authors :
Aurash B. Shahripour، نويسنده , , Mark S. Plummer، نويسنده , , Elizabeth A. Lunney، نويسنده , , Hans P Albrecht، نويسنده , , Sheryl J. Hays، نويسنده , , Catherine R. Kostlan، نويسنده , , Tomi K. Sawyer، نويسنده , , Nigel P.C Walker، نويسنده , , Kenneth D. Brady، نويسنده , , Hamish J. Allen، نويسنده , , Robert V. Talanian، نويسنده , , Winnie W. Wong، نويسنده , , Christine Humblet، نويسنده ,
Abstract :
A novel class of reversible inhibitors of Interleukin-1β-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure–activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.
