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Bioorg Med Chem. 2018 Aug 7;26(14):4310-4319. doi: 10.1016/j.bmc.2018.07.032. Epub 2018 Jul 19.

Selective inhibition of human cathepsin S by 2,4,6-trisubstituted 1,3,5-triazine analogs.

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Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France.
INSERM, UMR 1100, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032 Tours cedex, France.
Université d'Orléans, CNRS, ICOA, UMR 7311, F-45067 Orléans, France. Electronic address:
Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.


We report herein the synthesis and biological evaluation of a new series of 2,4,6-trisubstituted 1,3,5-triazines as reversible inhibitors of human cysteine cathepsins. The desired products bearing morpholine and N-Boc piperidine, respectively, were obtained in three to four steps from commercially available trichlorotriazine. Seventeen hitherto unknown compounds were evaluated in vitro against various cathepsins for their inhibitory properties. Among them, compound 7c (4-(morpholin-4-yl)-6-[4-(trifluoromethoxy)anilino]-1,3,5-triazine-2-carbonitrile) was identified as the most potent and selective inhibitor of cathepsin S (Ki  =  2  ±  0.3 nM). Also 7c impaired the autocatalytic maturation of procathepsin S. Molecular docking studies support that 7c bound within the active site of cathepsin S, by interacting with Gly23, Cys25 and Trp26 (S1 subsite), with Asn67, Gly69 and Phe70 (S2 subsite) and with Gln19 (S1' pocket).


1,3,5-Triazine analogs; Cathepsins; Cysteine protease; Microwave irradiation; Protease inhibitors

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