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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

DOI

10.1016/j.ejmech.2013.08.027

Type

Journal article

Journal

European journal of medicinal chemistry

Publication Date

11/2013

Volume

69

Pages

244 - 261

Addresses

INSERM U761, Biostructures and Drug Discovery, France; Faculté de Pharmacie, Univ Lille Nord de France, 3 rue du Pr Laguesse, Lille F-59006, France; Institut Pasteur de Lille, IFR 142, Lille F-59021, France; PRIM, Lille F-59006, France.

Keywords

Humans, Zinc, Organometallic Compounds, Semicarbazides, Enzyme Inhibitors, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Drug Design, Models, Molecular, ADAM Proteins, ADAMTS5 Protein