title: Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group.
abstract: 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.
authors.affiliation: 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Maingot
authors.forename: Jamal
authors.initials: J
authors.lastname: Elbakali
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.forename: Damien
authors.initials: D
authors.lastname: Bosc
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cousaert
authors.forename: Agathe
authors.initials: A
authors.lastname: Urban
authors.forename: Gaelle
authors.initials: G
authors.lastname: Deglane
authors.forename: Bruno
authors.initials: B
authors.lastname: Villoutreix
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deprez-Poulain
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071116:ADAMTS5 Protein; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012663:Semicarbazides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D012663:Semicarbazides; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D015032:Zinc
keywords: 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