title: Synthesis and evaluation of novel 8,5-fused bicyclic peptidomimetic compounds as interleukin-1beta converting enzyme (ICE) inhibitors.
abstract: 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%).
authors.affiliation: The Procter & Gamble Pharmaceuticals, Inc., Cincinnati, OH 45241, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Soper
authors.forename: Justin X
authors.initials: JX
authors.lastname: Sheville
authors.forename: Steven V
authors.initials: SV
authors.lastname: O'Neil
authors.forename: Yili
authors.initials: Y
authors.lastname: Wang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Laufersweiler
authors.forename: Kofi A
authors.initials: KA
authors.lastname: Oppong
authors.forename: John A
authors.initials: JA
authors.lastname: Wos
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Mark W
authors.initials: MW
authors.lastname: Baize
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Amy N
authors.initials: AN
authors.lastname: Fancher
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Suchanek
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wang
authors.forename: William P
authors.initials: WP
authors.lastname: Schwecke
authors.forename: Charles A
authors.initials: CA
authors.lastname: Cruze
authors.forename: Maria
authors.initials: M
authors.lastname: Buchalova
authors.forename: Marina
authors.initials: M
authors.lastname: Belkin
authors.forename: Fred
authors.initials: F
authors.lastname: Wireko
authors.forename: Amanda
authors.initials: A
authors.lastname: Ritter
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Difei
authors.initials: D
authors.lastname: Wang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Demuth
mesh_terms: 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
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D011355:Prodrugs