title: Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors.
abstract: Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
authors.affiliation: Procter & Gamble Pharmaceuticals, Mason, OH 45040, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Soper
authors.forename: Justin
authors.initials: J
authors.lastname: Sheville
authors.forename: Steven V
authors.initials: SV
authors.lastname: O'Neil
authors.forename: Yili
authors.initials: Y
authors.lastname: Wang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Laufersweiler
authors.forename: Kofi A
authors.initials: KA
authors.lastname: Oppong
authors.forename: John A
authors.initials: JA
authors.lastname: Wos
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Amy N
authors.initials: AN
authors.lastname: Fancher
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Suchanek
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wang
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Demuth
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D053181:Caspase 8; D061945:Caspase Inhibitors; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004345:Drug Industry / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical
chemical_list: D000577:Amides; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006834:Hydrazines; D000620:Aminoimidazole Carboxamide; C505530:CASP8 protein, human; D053181:Caspase 8; D003546:Cysteine Endopeptidases