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

Therapeutic Approaches
Medicinal Chemistry

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

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;

Keywords

  • Animals
  • Asthma/ drug therapy
  • Asthma/ enzymology
  • Chemistry, Pharmaceutical/ methods
  • Disease Models, Animal
  • Drug Design
  • Enzyme Inhibitors/ pharmacology
  • Humans
  • Inflammation
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase 12/ metabolism
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Pulmonary Disease, Chronic Obstructive/ drug therapy
  • Pulmonary Disease, Chronic Obstructive/ enzymology
  • Structure-Activity Relationship
  • Sulfonamides/ chemistry
  • X-Rays

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