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 v...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2005-10, Vol.15 (19), p.4322
Hauptverfasser:	Laufersweiler, Michael C, Wang, Yili, Soper, David L, Suchanek, Maureen K, Fancher, Amy N, Lu, Wei, Wang, Richard L, Oppong, Kofi A, Ellis, Christopher D, Baize, Mark W, O'Neil, Steven V, Wos, John A, Demuth, Jr, Thomas P
Format:	Artikel
Sprache:	eng
Schlagworte:	Caspase Inhibitors Dipeptides - chemical synthesis Dipeptides - pharmacology Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - pharmacology Humans Immunologic Factors - chemical synthesis Immunologic Factors - pharmacology Inhibitory Concentration 50 Molecular Mimicry Monocytes Pyrimidinones - chemical synthesis Pyrimidinones - pharmacology Pyrroles - chemical synthesis Pyrroles - pharmacology Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0960-894X