- Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)
-
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.
- Wu, Yuchuan,Li, Jianchang,Wu, Junjun,Morgan, Paul,Xu, Xin,Rancati, Fabio,Vallese, Stefania,Raveglia, Luca,Hotchandani, Rajeev,Fuller, Nathan,Bard, Joel,Cunningham, Kristina,Fish, Susan,Krykbaev, Rustem,Tam, Steve,Goldman, Samuel J.,Williams, Cara,Mansour, Tarek S.,Saiah, Eddine,Sypek, Joseph,Li, Wei
-
scheme or table
p. 138 - 143
(2012/02/16)
-
- Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma
-
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 go
- Li, Wei,Li, Jianchang,Wu, Yuchuan,Rancati, Fabio,Vallese, Stefania,Raveglia, Luca,Wu, Junjun,Hotchandani, Rajeev,Fuller, Nathan,Cunningham, Kristina,Morgan, Paul,Fish, Susan,Krykbaev, Rustem,Xu, Xin,Tam, Steve,Goldman, Samuel J.,Abraham, William,Williams, Cara,Sypek, Joseph,Mansour, Tarek S.
-
supporting information; experimental part
p. 5408 - 5419
(2010/02/28)
-
- TRICYCLIC COMPOUNDS AS MATRIX METALLOPROTEINASE INHIBITORS
-
The present invention relates to compositions of the formula (I): and pharmaceutically acceptable salts, hydrates, or esters thereof, wherein R1, R2, R3, R4, R5, X, and Y are as defined herein. The present teachings also provide methods of making the compounds of formula I, and methods of treating pathologic conditions or disorders mediated wholly or in part by matrix metalloproteinases, such as asthma and chronic obstructive pulmonary disease, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal (e.g., a human) in need thereof.
- -
-
Page/Page column 103; 121
(2008/12/05)
-