Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4233-6. doi: 10.1016/j.bmcl.2006.05.076.

David L Soper ¹, Justin Sheville, Steven V O'Neil, Yili Wang, Michael C Laufersweiler, Kofi A Oppong, John A Wos, Christopher D Ellis, Amy N Fancher, Wei Lu, Maureen K Suchanek, Richard L Wang, Biswanath De, Thomas P Demuth Jr

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Affiliation

1 Procter & Gamble Pharmaceuticals, Mason, OH 45040, USA.

PMID: 16782334 DOI: 10.1016/j.bmcl.2006.05.076

Abstract

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases Caspase-3 and Caspase-8, although several dual-acting inhibitors of ICE and Caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).

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