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Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.

Original publication




Journal article


Eur J Med Chem

Publication Date





244 - 261


3,3′,5,5′-tetramethylbenzidine, ADAMTS-5, AcOH, Acylthiosemicarbazide, Aggrecanase, Boc, CH(3)CN, DCE, DCM, DIEA, DMF, DMP, DMSO, Dess–Martin periodinane, EDCI, Et(3)N, EtOAc, EtOH, HOBt, Library, MeOH, N,N-diisopropylethylamine, N-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, OA, PBS, PTSA, SAR, TACE, THF, TMB, a disintegrin and metalloproteinase with thrombospondin motifs 5, acetic acid, acetonitrile, dichloroethane, dichloromethane, dimethylformamide, dimethylsulfoxide, ethanol, ethyl acetate, methanol, osteoarthritis, para-toluenesulfonic acid, phosphate buffered saline, room temperature, rt, structure–activity relationship, tert-butoxycarbonyl, tetrahydrofuran, triethylamine, tumor necrosis factor-α-converting enzyme, ADAM Proteins, ADAMTS5 Protein, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors, Humans, Models, Molecular, Molecular Structure, Organometallic Compounds, Semicarbazides, Structure-Activity Relationship, Zinc