Synthesis and kinetic evaluation of ethyl acrylate and vinyl sulfone derived inhibitors for human cysteine cathepsins. Issue 11 (15th June 2018)

• Record Type: Journal Article
• Authors: Breuer, Christian; Lemke, Carina; Schmitz, Janina; Bartz, Ulrike; Gütschow, Michael
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 11(2018)
• Page Start: 2008
• Page End: 2012
• Publication Date: 2018-06-15
• Subjects: Cathepsins -- Cysteine proteases -- Horner-Wadsworth-Emmons olefination -- Irreversible inhibition -- Michael acceptors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.05.005
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Ten inhibitors of the phenyl vinyl sulfone or ethyl acrylate chemotype were prepared. The potency against four human cathepsins was examined. The thiol reactivity under physiological conditions was estimated. Compound6c was identified as a potent cathepsin S inactivator. Abstract: 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. Compound6c 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 −1 s −1 .