Silva, Taynara L. [1, 2] ; dos Santos, Deborah A.  ; de Jesus, Hugo C. R.  ; Bromme, Dieter  ; Fernandes, Joao B.  ; Paixao, Marcio W.  ; Correa, Arlene G.  ; Vieira, Paulo C. [3, 4]
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.
1 Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos, SP, Brazil
2 Faculty of Dentistry and UBC Center for Blood Research, 2350 Health Sciences Mall, Vancouver, BC V6T1Z3 Canada
3 Centre of Excellence for Research on Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos, SP, Brazil
4 School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, 14040-903 Ribeirão Preto, SP, Brazil