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.
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S. In silico design, synthesis and biochemical characterization / Lemke, Carina; Cianni, Lorenzo; Feldmann, Christian; Gilberg, Erik; Yin, Jiafei; Dos Reis Rocho, Fernanda; De Vita, Daniela; Bartz, Ulrike; Bajorath, Jürgen; Montanari, Carlos A.; Gütschow, Michael. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 30:18(2020). [10.1016/j.bmcl.2020.127420]
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S. In silico design, synthesis and biochemical characterization
De Vita, Daniela;
2020
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.File | Dimensione | Formato | |
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