Structure-based design of nonpeptide inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1).
A novel class of reversible inhibitors of Interleukin-1beta-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.
Shahripour
Aurash B
AB
Department of Medicinal Chemistry, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. aurash.shahripour@pfizer.com
Plummer
Mark S
MS
Lunney
Elizabeth A
EA
Albrecht
Hans P
HP
Hays
Sheryl J
SJ
Kostlan
Catherine R
CR
Sawyer
Tomi K
TK
Walker
Nigel P C
NP
Brady
Kenneth D
KD
Allen
Hamish J
HJ
Talanian
Robert V
RV
Wong
Winnie W
WW
Humblet
Christine
C
D061945:Caspase Inhibitors; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors