title: Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.
abstract: Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.forename: Isabella
authors.initials: I
authors.lastname: Pugliesi
authors.forename: Matteo
authors.initials: M
authors.lastname: Morelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Casalini
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Robert
authors.initials: R
authors.lastname: Visse
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Federico
authors.initials: F
authors.lastname: da Settimo
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D053509:Matrix Metalloproteinase 13