Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors

[Display omitted] Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in t...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2020-08, Vol.28 (15), p.115597-115597, Article 115597
Main Authors: Silva, Taynara L., dos Santos, Deborah A., de Jesus, Hugo C.R., Brömme, Dieter, Fernandes, João B., Paixão, Marcio W., Corrêa, Arlene G., Vieira, Paulo C.
Format: Article
Language:English
Subjects:
Cathepsin K
Cysteine proteases
Inhibitors
Peptidomimetics
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Summary:[Display omitted] Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2020.115597