4.7 Article

Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Journal

BIOORGANIC & MEDICINAL CHEMISTRY
Volume 29, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115827

Keywords

Human cysteine proteases; cathepsin B; cathepsin L; Nitrile inhibitors

Funding

  1. Fundacao de Amparo a Pesquisa do Estado de Sao Paulo -FAPESP [2013/18009-4, 2016/07946-5, 2018/03985-1]
  2. Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [001]
  3. National Council for Scientific and Technological Development - CNPq [304030/2018-0]

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In this study, a new set of peptide-like nitrile-based cathepsin inhibitors were synthesized using a knowledge-based design approach. Three compounds showed nanomolar inhibition of CatB with selectivity over other cysteine proteases. Through a structure-based design, selective CatB inhibition was achieved, and successful bioisosteric replacement of the amide bond for a sulfonamide one was demonstrated.
Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e -> 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins.

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