Synthesis and evaluation of tricyclic pyrrolopyrimidinones as dipeptide mimetics: inhibition of interleukin-1beta-converting enzyme.
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.
Laufersweiler
Michael C
MC
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA. Laufersweiler.mc@pg.com
Wang
Yili
Y
Soper
David L
DL
Suchanek
Maureen K
MK
Fancher
Amy N
AN
Lu
Wei
W
Wang
Richard L
RL
Oppong
Kofi A
KA
Ellis
Christopher D
CD
Baize
Mark W
MW
O'Neil
Steven V
SV
Wos
John A
JA
Demuth
Thomas P
TP
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
D061945:Caspase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007155:Immunologic Factors; D011744:Pyrimidinones; D011758:Pyrroles