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

• Published in: Bioorganic & medicinal chemistry Vol. 29; p. 115827
• Main Authors: Cianni, Lorenzo, Rocho, Fernanda Dos Reis, Bonatto, Vinícius, Martins, Felipe Cardoso Prado, Lameira, Jerônimo, Leitão, Andrei, Montanari, Carlos A., Shamim, Anwar
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2021
• Subjects: cathepsin B; cathepsin L; Human cysteine proteases; Nitrile inhibitors; Human cysteine proteases; Nitrile inhibitors; cathepsin L; cathepsin B
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115827

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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.