Discovery and kinetic evaluation of 6-substituted 4-benzylthio-1,3, 5-triazin-2(1H)-ones as inhibitors of cathepsin B

作者：Sosic Izidor; Mirkovic Bojana; Turk Samo; Stefane Bogdan; Kos Janko; Gobec Stanislav^*

来源：European Journal of Medicinal Chemistry, 2011, 46(9): 4648-4656.

DOI：10.1016/j.ejmech.2011.08.005

• Cathepsin B
• Cysteine protease
• Noncovalent inhibitors
• 1,3,5-Triazine-2(1H)-ones
• Partial mixed-type inhibition

Cathepsin B is a lysosomal cysteine protease that has various physiological and pathophysiological functions. We present here the discovery of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B. starting from screening of a library of variously 2,4,6-trisubstituted 1,3,5-triazines and 1,3,5-triazin-2(1H)-ones on three different human cathepsins. The synthesis and enzymatic evaluation of a focused library of new 1,3,5-triazin-2(1H)-ones is also described. The detailed kinetics analyses have shown that these compounds can act as reversible, partial mixed-type inhibitors of cathepsin B, with K-i and K-i' values in the low micromolar range. The inhibitory activities of selected compounds were also assessed against two related cysteine proteases, cathepsin H and cathepsin L, to estimate their selectivity; these compounds have a selective profile for catB and catL over catH.

• 出版日期2011-9