title: Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD).
abstract: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.
authors.affiliation: Pfizer Global Research & Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA. charliewu09@yahoo.com
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Jianchang
authors.initials: J
authors.lastname: Li
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Fabio
authors.initials: F
authors.lastname: Rancati
authors.forename: Stefania
authors.initials: S
authors.lastname: Vallese
authors.forename: Luca
authors.initials: L
authors.lastname: Raveglia
authors.forename: Rajeev
authors.initials: R
authors.lastname: Hotchandani
authors.forename: Nathan
authors.initials: N
authors.lastname: Fuller
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: Kristina
authors.initials: K
authors.lastname: Cunningham
authors.forename: Susan
authors.initials: S
authors.lastname: Fish
authors.forename: Rustem
authors.initials: R
authors.lastname: Krykbaev
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Joseph
authors.initials: J
authors.lastname: Sypek
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014965:X-Rays
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053508:Matrix Metalloproteinase 12