1. Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L.
- Author
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Cianni L, Rocho FDR, Bonatto V, Martins FCP, Lameira J, Leitão A, Montanari CA, and Shamim A
- Subjects
- Amides chemical synthesis, Amides chemistry, Amines chemical synthesis, Amines chemistry, Cathepsin B metabolism, Cathepsin L metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Molecular Dynamics Simulation, Molecular Structure, Structure-Activity Relationship, Amides pharmacology, Amines pharmacology, Cathepsin B antagonists & inhibitors, Cathepsin L antagonists & inhibitors, Drug Design, Enzyme Inhibitors pharmacology
- Abstract
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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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