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ChemMedChem. 2010 May 3;5(5):730-8. doi: 10.1002/cmdc.200900531.

A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety.

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National Institutes of Health, National Human Genome Research Institute, NIH Chemical Genomics Center, Rockville, Maryland 20850, USA.


Herein, we examine the potential of a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of caspase 1 (IC(50) values < or =1 nM). Examination of these novel small molecules against a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition over other caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings, including in vivo analyses.

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