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N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization.

Authors
  • Lemke, Carina1
  • Cianni, Lorenzo2
  • Feldmann, Christian3
  • Gilberg, Erik3
  • Yin, Jiafei1
  • Dos Reis Rocho, Fernanda4
  • de Vita, Daniela4
  • Bartz, Ulrike5
  • Bajorath, Jürgen6
  • Montanari, Carlos A7
  • Gütschow, Michael8
  • 1 Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. , (Germany)
  • 2 Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany; Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trablhador Sao-carlense 400, BR-13560-970 Sao Carlos, Brazil. , (Brazil)
  • 3 Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany. , (Germany)
  • 4 Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trablhador Sao-carlense 400, BR-13560-970 Sao Carlos, Brazil. , (Brazil)
  • 5 Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, 53359 Rheinbach, Germany. , (Germany)
  • 6 Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany. Electronic address: [email protected] , (Germany)
  • 7 Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trablhador Sao-carlense 400, BR-13560-970 Sao Carlos, Brazil. Electronic address: [email protected] , (Brazil)
  • 8 Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Jul 17, 2020
Volume
30
Issue
18
Pages
127420–127420
Identifiers
DOI: 10.1016/j.bmcl.2020.127420
PMID: 32763808
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Ki = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Ki = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S. Copyright © 2020 Elsevier Ltd. All rights reserved.

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