title: Synthesis and evaluation of tricyclic pyrrolopyrimidinones as dipeptide mimetics: inhibition of interleukin-1beta-converting enzyme.
abstract: The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.
authors.affiliation: Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA. Laufersweiler.mc@pg.com
authors.forename: Michael C
authors.initials: MC
authors.lastname: Laufersweiler
authors.forename: Yili
authors.initials: Y
authors.lastname: Wang
authors.forename: David L
authors.initials: DL
authors.lastname: Soper
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Suchanek
authors.forename: Amy N
authors.initials: AN
authors.lastname: Fancher
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wang
authors.forename: Kofi A
authors.initials: KA
authors.lastname: Oppong
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Mark W
authors.initials: MW
authors.lastname: Baize
authors.forename: Steven V
authors.initials: SV
authors.lastname: O'Neil
authors.forename: John A
authors.initials: JA
authors.lastname: Wos
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Demuth
mesh_terms: D061945:Caspase Inhibitors; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D009000:Monocytes; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D061945:Caspase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007155:Immunologic Factors; D011744:Pyrimidinones; D011758:Pyrroles