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

Medicinal Chemistry


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.


Boxer, Matthew B; Quinn, Amy M; Shen, Min; Jadhav, Ajit; Leister, William; Simeonov, Anton; Auld, Douglas S; Thomas, Craig;


  • 4-Aminobenzoic Acid/ chemistry
  • Animals
  • Binding Sites
  • Caspase 1/ metabolism
  • Caspase Inhibitors
  • Catalytic Domain
  • Computer Simulation
  • Cysteine Proteinase Inhibitors/ chemical synthesis
  • Cysteine Proteinase Inhibitors/ chemistry
  • Cysteine Proteinase Inhibitors/ pharmacokinetics
  • Dipeptides/ chemistry
  • Humans
  • Microsomes, Liver/ metabolism
  • Propionates/ chemical synthesis
  • Propionates/ chemistry
  • Propionates/ pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • para-Aminobenzoates

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