title: N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.
abstract: Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.forename: Francesca
authors.initials: F
authors.lastname: Casalini
authors.forename: Stanislava I
authors.initials: SI
authors.lastname: Avramova
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cercignani
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Ngee-Han
authors.initials: NH
authors.lastname: Lim
authors.forename: Robert
authors.initials: R
authors.lastname: Visse
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry; D000072198:ADAM17 Protein; D002356:Cartilage / Q000378:metabolism; D015195:Drug Design; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D053511:Matrix Metalloproteinase 14; D000072198:ADAM17 Protein