Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors.
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).
Soper
David L
DL
Procter & Gamble Pharmaceuticals, Mason, OH 45040, USA.
Sheville
Justin
J
O'Neil
Steven V
SV
Wang
Yili
Y
Laufersweiler
Michael C
MC
Oppong
Kofi A
KA
Wos
John A
JA
Ellis
Christopher D
CD
Fancher
Amy N
AN
Lu
Wei
W
Suchanek
Maureen K
MK
Wang
Richard L
RL
De
Biswanath
B
Demuth
Thomas P
TP
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
D000577:Amides; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006834:Hydrazines; D000620:Aminoimidazole Carboxamide; C505530:CASP8 protein, human; D053181:Caspase 8; D003546:Cysteine Endopeptidases