Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors

• Published in: Journal of medicinal chemistry Vol. 45; no. 25; pp. 5471 - 5482
• Main Authors: Ward, Yancey D, Thomson, David S, Frye, Leah L, Cywin, Charles L, Morwick, Tina, Emmanuel, Michel J, Zindell, Renée, McNeil, Daniel, Bekkali, Younes, Hrapchak, Matt, DeTuri, Molly, Crane, Kathy, White, Della, Pav, Susan, Wang, Yong, Hao, Ming-Hong, Grygon, Christine A, Labadia, Mark E, Freeman, Dorothy M, Davidson, Walter, Hopkins, Jerry L, Brown, Maryanne L, Spero, Denice M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05-12-2002
• Subjects: B-Lymphocytes - drug effects; Binding, Competitive; Biological and medical sciences; Cathepsins - chemical synthesis; Cathepsins - chemistry; Cathepsins - pharmacology; Cell Line; Crystallography, X-Ray; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Immunomodulators; Kinetics; Medical sciences; Models, Molecular; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Nitrile; Peptides; Cysteine endopeptidases; Liquid phase; Morpholine derivatives; Modeling; Structure activity relation; Molecular model; Ureas; Chemical synthesis; Human; Enzyme; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Cathepsin S; X ray diffraction; In vitro; Peptidases; Dipeptides; Hydrolases; Carboxamide; Reversibility; Peptide synthesis; Kinetics; Solid phase; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020209i

The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.