Synthesis and evaluation of unsaturated caprolactams as interleukin-1beta converting enzyme (ICE) inhibitors.
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
Wang
Yili
Y
Procter & Gamble Pharmaceuticals, Inc., 8700 Mason-Montgomery Road, Mason, OH 45040, USA.
O'Neil
Steven V
SV
Wos
John A
JA
Oppong
Kofi A
KA
Laufersweiler
Michael C
MC
Soper
David L
DL
Ellis
Christopher D
CD
Baize
Mark W
MW
Fancher
Amy N
AN
Lu
Wei
W
Suchanek
Maureen K
MK
Wang
Richard L
RL
Schwecke
William P
WP
Cruze
Charles A
CA
Buchalova
Maria
M
Belkin
Marina
M
De
Biswanath
B
Demuth
Thomas P
TP
D000818:Animals; D001682:Biological Availability; D002209:Caprolactam / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061945:Caspase Inhibitors; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000138:chemical synthesis* / Q000494:pharmacology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D015843:Serpins; D014764:Viral Proteins; D002209:Caprolactam; C074641:interleukin-1beta-converting enzyme inhibitor