title: N-O-isopropyl sulfonamido-based hydroxamates: kinetic characterisation of a series of MMP-12/MMP-13 dual target inhibitors.
abstract: Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases known to play key roles in extracellular matrix (ECM) breakdown disorders, such as the two main forms of arthritis, rheumatoid arthritis (RA) and osteoarthritis (OA). MMP-13 (collagenase 3) is the leading MMP involved in cartilage degradation through its particular ability to cleave type-II collagen and as such plays a pivotal role in the pathogenesis of these diseases. Here we report the kinetic characterisation of N-O-isopropyl sulfonamido-based hydroxamates, potent inhibitors of MMP-13 and MMP-12, bearing different P1 and P1' substituents. One of these compounds proved to be a potent (4 ≤ K(i) ≤ 5 nM) slow-binding inhibitor towards MMP-13 and MMP-12, with very favourable low association (10(4) M(-1) s(-1)) and dissociation constants (10(-4) s(-1)). Moreover, this compound exhibited a good selectivity for MMP-13 and MMP-12 over MMP-1, MMP-3, MMP-7, MMP-8 and, even to a minor extent, MMP-2. A molecular-docking study carried out using the experimentally-derived X-ray crystal structure of MMP-12 (PDB ID: 3F17) revealed critical hydrogen bonding of the hydroxamate and the sulfonamide moieties with key active site residues. Since also MMP-12 is involved in RA, this MMP-13/MMP-12 dual target inhibitor could be a valid candidate for the treatment of this pathology.
authors: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Salvatore
authors: S
authors: Santamaria
authors: Elisa
authors: E
authors: Nuti
authors: Giovanni
authors: G
authors: Cercignani
authors: Luciana
authors: L
authors: Marinelli
authors: Valeria
authors: V
authors: La Pietra
authors: Ettore
authors: E
authors: Novellino
authors: Armando
authors: A
authors: Rossello
mesh_terms: D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007700:Kinetics; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053509:Matrix Metalloproteinase 13; D053508:Matrix Metalloproteinase 12