Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors

The synthesis and SAR of the first succinyl-nitrile-based compounds as Cathepsin S inhibitors are described. The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzy...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 17; no. 9; pp. 2465 - 2469
Main Authors:	Bekkali, Younes, Thomson, David S., Betageri, Raj, Emmanuel, Michel J., Hao, Ming-Hong, Hickey, Eugene, Liu, Weimin, Patel, Usha, Ward, Yancey D., Young, Erick R.R., Nelson, Richard, Kukulka, Alison, Brown, Maryanne L., Crane, Kathy, White, Della, Freeman, Dorothy M., Labadia, Mark E., Wildeson, Jessi, Spero, Denice M.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-05-2007 Elsevier
Subjects:	Analytical, structural and metabolic biochemistry Biological and medical sciences Cat S Catalytic Domain Cathepsin S Cathepsins - antagonists & inhibitors Chemistry, Pharmaceutical - methods Dipeptides - chemistry Drug Design Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Humans Hydrolases Medical sciences Miscellaneous Models, Chemical Molecular Conformation Nitrile Nitriles - chemistry Nitriles - classification Peptides - chemistry Pharmacology. Drug treatments Piperidines - chemistry Pyrrolidines - chemistry Structure-Activity Relationship Succinyl Nitrile Cathepsin S Cat S Succinyl Cyclohexane derivatives Enzyme Cysteine endopeptidases Enzyme inhibitor In vitro Peptidases Structure activity relation Animal Bicyclic compound Hydrolases Carboxamide Aromatic compound Chemical synthesis Monocyclic compound
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Summary:	The synthesis and SAR of the first succinyl-nitrile-based compounds as Cathepsin S inhibitors are described. The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the α-carbon of the P1 residue.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.02.046