title: Discovery and kinetic evaluation of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Bojana
authors.initials: B
authors.lastname: Mirković
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Bogdan
authors.initials: B
authors.lastname: Štefaneb
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014227:Triazines; D002401:Cathepsin B