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

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

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):138-43. doi: 10.1016/j.bmcl.2011.11.046.
Yuchuan Wu 1,  Jianchang Li,  Junjun Wu,  Paul Morgan,  Xin Xu,  Fabio Rancati,  Stefania Vallese,  Luca Raveglia,  Rajeev Hotchandani,  Nathan Fuller,  Joel Bard,  Kristina Cunningham,  Susan Fish,  Rustem Krykbaev,  Steve Tam,  Samuel J Goldman,  Cara Williams,  Tarek S Mansour,  Eddine Saiah,  Joseph Sypek,  Wei Li
Affiliations

Affiliation

  • 1 Pfizer Global Research & Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA. [email protected]
PMID: 22153340 DOI: 10.1016/j.bmcl.2011.11.046
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.

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