Synthesis and evaluation of thiazepines as interleukin-1beta converting enzyme (ICE) inhibitors.
A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.
Ellis
Christopher D
CD
Procter and Gamble Pharmaceuticals Incorporated, 8700 Mason-Montgomery Road, Mason, OH 45040, USA. ellis.cd@pg.com
Oppong
Kofi A
KA
Laufersweiler
Michael C
MC
O'Neil
Steven V
SV
Soper
David L
DL
Wang
Yili
Y
Wos
John A
JA
Fancher
Amy N
AN
Lu
Wei
W
Suchanek
Maureen K
MK
Wang
Richard L
RL
De
Biswanath
B
Demuth
Thomas P
TP
D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D013841:Thiazepines; D020170:Caspase 1