title: Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma.
abstract: MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.
authors.affiliation: Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. weili@wyeth.com
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jianchang
authors.initials: J
authors.lastname: Li
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wu
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: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Rajeev
authors.initials: R
authors.lastname: Hotchandani
authors.forename: Nathan
authors.initials: N
authors.lastname: Fuller
authors.forename: Kristina
authors.initials: K
authors.lastname: Cunningham
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.forename: Susan
authors.initials: S
authors.lastname: Fish
authors.forename: Rustem
authors.initials: R
authors.lastname: Krykbaev
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: William
authors.initials: W
authors.lastname: Abraham
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: Joseph
authors.initials: J
authors.lastname: Sypek
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology; D055808:Drug Discovery; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors