title: Design, synthesis and biological evaluation of a library of thiocarbazates and their activity as cysteine protease inhibitors.
abstract: Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.
authors.affiliation: Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Liu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Myers
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Beavers
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Benedetti
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
mesh_terms: D002851:Chromatography, High Pressure Liquid; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D013438:Sulfhydryl Compounds