Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors.

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Ward YD, Thomson DS, Frye LL, Cywin CL, Morwick T, Emmanuel MJ, Zindell R, McNeil D, Bekkali Y, Girardot M, Hrapchak M, DeTuri M, Crane K, White D, Pav S, Wang Y, Hao MH, Grygon CA, Labadia ME, Freeman DM, Davidson W, Hopkins JL, Brown ML, Spero DM

Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors.

J Med Chem. 2002 Dec 5;45(25):5471-82.

PubMed ID

12459015 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morpholine-4-Carboxylic Acid [1s-(2-Benzyloxy-1r-Cyano-Ethylcarbamoyl)-3-Methyl-Butyl]Amide	Cathepsin S	Kd (nM)	0.3	N/A	N/A	Details
Morpholine-4-Carboxylic Acid [1s-(2-Benzyloxy-1r-Cyano-Ethylcarbamoyl)-3-Methyl-Butyl]Amide	Cathepsin S	IC 50 (nM)	19	N/A	N/A	Details