Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)

详细信息    查看全文

• 作者：Yuchuan Wu^a ; ^{charliewu09@yahoo.com} ; Jianchang Li^a ; Junjun Wu^a ; Paul Morgan^a ; Xin Xu^a ; Fabio Rancati^b ; Stefania Vallese^b ; Luca Raveglia^b ; Rajeev Hotchandani^a ; Nathan Fuller^a ; Joel Bard^a ; Kristina Cunningham^a ; Susan Fish^a ; Rustem Krykbaev^a ; Steve Tam^a ; Samuel J. Goldman^a ; Cara Williams^a ; Tarek S. Mansour^a ; Eddine Saiah^a ; Joseph Sypek^a ; Wei Li^a
• 关键词：MMP-12 ; COPD ; SAR ; Dibenzofuran
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 January, 2012
• 年：2012
• 卷：22
• 期：1
• 页码：138-143
• 全文大小：1493 K

文摘

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.