title: Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13.
abstract: The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.
authors.affiliation: Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139, USA.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Tommasi
authors.forename: Sven
authors.initials: S
authors.lastname: Weiler
authors.forename: Leslie W
authors.initials: LW
authors.lastname: McQuire
authors.forename: Olivier
authors.initials: O
authors.lastname: Rogel
authors.forename: Mark
authors.initials: M
authors.lastname: Chambers
authors.forename: Kirk
authors.initials: K
authors.lastname: Clark
authors.forename: John
authors.initials: J
authors.lastname: Doughty
authors.forename: James
authors.initials: J
authors.lastname: Fang
authors.forename: Vishwas
authors.initials: V
authors.lastname: Ganu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grob
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldberg
authors.forename: Robert
authors.initials: R
authors.lastname: Goldstein
authors.forename: Stacey
authors.initials: S
authors.lastname: Lavoie
authors.forename: Raviraj
authors.initials: R
authors.lastname: Kulathila
authors.forename: William
authors.initials: W
authors.lastname: Macchia
authors.forename: Richard
authors.initials: R
authors.lastname: Melton
authors.forename: Clayton
authors.initials: C
authors.lastname: Springer
authors.forename: Marc
authors.initials: M
authors.lastname: Walker
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhu
authors.forename: Michael
authors.initials: M
authors.lastname: Shultz
mesh_terms: D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013449:Sulfonamides