N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.
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.
Nuti
Elisa
E
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Casalini
Francesca
F
Avramova
Stanislava I
SI
Santamaria
Salvatore
S
Cercignani
Giovanni
G
Marinelli
Luciana
L
La Pietra
Valeria
V
Novellino
Ettore
E
Orlandini
Elisabetta
E
Nencetti
Susanna
S
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Lim
Ngee-Han
NH
Visse
Robert
R
Nagase
Hideaki
H
Rossello
Armando
A
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
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