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