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

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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.

Graphical abstract

X-ray co-structure of compound 26.

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Acknowledgments

The authors are grateful to Dr. Nelson Huang and Ms. Ning Pan for LC-MS measurements, Drs. Walter Massefski and Vasilios Marathias for the contribution of NMR analysis, Drs. John Kubera and Franklin Schlerman for the lung inflammation experiments and Drs. Iain McFadyen and Diane Joseph-McCarthy for molecular modeling help.

References and notes (15)

  • S. Mukhopadhyay et al.

    J. Allergy Clin. Immunol.

    (2010)
  • Y. Muramoto et al.

    Daigaku Kogakubu Kenkyu Hokoku

    (1991)
  • B.R. Celli et al.

    Eur. Respir. J.

    (2004)
  • R.A. Pauwel et al.

    Lancet

    (2004)
  • A. Jemal et al.

    JAMA

    (2005)
  • A.S. Buist

    Proc. Am. Thorac. Soc.

    (2008)
  • I. Vanlaere et al.

    Clin. Microbiol. Rev.

    (2009)
There are more references available in the full text version of this article.

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