Noncovalent tripeptidyl benzyl- and cyclohexyl-amine inhibitors of the cysteine protease caspase-1

Reik Löser; Giovanni Abbenante; Praveen K Madala; Maria Halili; Giang T Le; David P Fairlie

doi:10.1021/jm901790w

Noncovalent tripeptidyl benzyl- and cyclohexyl-amine inhibitors of the cysteine protease caspase-1

J Med Chem. 2010 Mar 25;53(6):2651-5. doi: 10.1021/jm901790w.

Authors

Reik Löser¹, Giovanni Abbenante, Praveen K Madala, Maria Halili, Giang T Le, David P Fairlie

Affiliation

¹ Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.

PMID: 20170165
DOI: 10.1021/jm901790w

Abstract

Potent and noncovalent inhibitors of caspase-1 were produced by incorporating a secondary amine (reduced amide) isostere in place of the conventional electrophile (e.g., aldehyde) that normally confers high potency to cysteine protease inhibitors. Benzyl- or cyclohexylamines produced potent, reversible, and competitive inhibitors that were selective for caspase-1 (e.g., K(i) = 47 nM) over caspases 3 and 8 with minimal cytotoxicity. Unlike most cysteine protease inhibitors, these compounds do not react covalently and indiscriminately with thiols.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Benzene / chemistry
Caspase 1 / chemistry
Caspase 1 / metabolism
Caspase Inhibitors*
Cell Survival / drug effects
Cyclohexylamines / chemical synthesis
Cyclohexylamines / chemistry
Cyclohexylamines / pharmacology
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
HT29 Cells
Humans
Kinetics
Models, Chemical
Models, Molecular
Molecular Structure
Protein Binding
Protein Structure, Tertiary

Substances

Amines
Caspase Inhibitors
Cyclohexylamines
Cysteine Proteinase Inhibitors
Caspase 1
Benzene