Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group

• Inhibitors of aggrecanases are described.
• A library of 920 acylthiosemicarbazides allowed structure–activity relationships.
• Zing binding group makes 3 key interactions.
• Derivative 35 is selective and inhibits degradation of full-aggrecan.

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.

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