Synthesis and evaluation of novel 8,5-fused bicyclic peptidomimetic compounds as interleukin-1beta converting enzyme (ICE) inhibitors.
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).
Soper
David L
DL
The Procter & Gamble Pharmaceuticals, Inc., Cincinnati, OH 45241, USA.
Sheville
Justin X
JX
O'Neil
Steven V
SV
Wang
Yili
Y
Laufersweiler
Michael C
MC
Oppong
Kofi A
KA
Wos
John A
JA
Ellis
Christopher D
CD
Baize
Mark W
MW
Chen
Jack J
JJ
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
Wireko
Fred
F
Ritter
Amanda
A
De
Biswanath
B
Wang
Difei
D
Demuth
Thomas P
TP
D000818:Animals; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D019086:Bridged Bicyclo Compounds, Heterocyclic; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D011355:Prodrugs