Inhibition of interleukin-1beta converting enzyme (ICE or caspase 1) by aspartyl acyloxyalkyl ketones and aspartyl amidooxyalkyl ketones.
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Galatsis
Paul
P
Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. paul.galatsis@pfizer.com
Caprathe
Bradley
B
Downing
Dennis
D
Gilmore
John
J
Harter
William
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Hays
Sheryl
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Kostlan
Catherine
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Linn
Kristin
K
Lunney
Elizabeth
E
Para
Kim
K
Thomas
Anthony
A
Warmus
Joseph
J
Allen
Hamish
H
Brady
Kenneth
K
Talanian
Robert
R
Walker
Nigel
N
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007659:Ketones