Synthesis and kinetic evaluation of ethyl acrylate and vinyl sulfone derived inhibitors for human cysteine cathepsins

  • A series of inhibitors targeting human cathepsins have been designed and synthesized following a combinatorial approach. The compounds bear an α,β-unsaturated phenyl vinyl sulfone or ethyl acrylate warhead and a peptidomimetic portion aligned to the non-primed binding region. Biochemical evaluation toward four human cathepsins was carried out and the kinetic characterization confirmed an irreversible mode of inhibition. Compound 6c combining the most advantageous building blocks for cathepsin S inhibition was identified as a potent cathepsin S inactivator exhibiting a second-order rate constant of 30600 M-1s-1.

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Metadaten
Document Type:Article
Language:English
Parent Title (English):Bioorg Med Chem Lett. (Bioorganic & Medicinal Chemistry Letters)
ISSN:0960-894X
DOI:10.1016/j.bmcl.2018.05.005
Publisher:Elsevier
Place of publication:Amsterdam
Date of first publication:2018/05/04
Submission status:accepted
Tag:Cathepsins; Cysteine proteases; Horner-Wadsworth-Emmons olefination Irreversible inhibition; Michael acceptors
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Dewey Decimal Classification (DDC):500 Naturwissenschaften und Mathematik / 540 Chemie / 540 Chemie und zugeordnete Wissenschaften
Entry in this database:2018/05/09

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