Peptidyl allyl sulfones: a new class of inhibitors for clan CA cysteine proteases

• Published in: Bioorganic & medicinal chemistry 2004-10, Vol.12 (19), p.5203-5211
• Main Authors: Götz, Marion G., Caffrey, Conor R., Hansell, Elizabeth, McKerrow, James H., Powers, James C.
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cathepsins; Cattle; Cruzain; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - drug effects; Cysteine protease inhibitor; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacology; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Enzymes and enzyme inhibitors; Erythrocytes - enzymology; Fundamental and applied biological sciences. Psychology; Hydrolases; Inhibitory Concentration 50; Kinetics; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Vinyl sulfone
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.07.016

[Display omitted] A new series of peptidyl allyl sulfone inhibitors was discovered while trying to synthesize epoxy sulfone inhibitors from vinyl sulfones using basic oxidizing conditions. The various dipeptidyl allyl sulfones were evaluated with calpain I, papain, cathepsins B and L, cruzain and rhodesain and found to be potent inhibitors. In comparison to the previously developed class of vinyl sulfone inhibitors, the novel dipeptidyl allyl sulfones were more potent inhibitors than the corresponding dipeptidyl vinyl sulfones. It was observed that the stereochemistry of the vinyl sulfone precursor played a role in the potency of the dipeptidyl allyl sulfone inhibitor.