Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma

Wei Li, Jianchang Li, Yuchuan Wu, Fabio Rancati, Stefania Vallese, Luca Raveglia, Junjun Wu, Rajeev Hotchandani, Nathan Fuller, Kristina Cunningham, Paul Morgan, Susan Fish, Rustem Krykbaev, Xin Xu, Steve Tam, Samuel J. Goldman, William Abraham, Cara Williams, Joseph Sypek, Tarek S. Mansour

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.

Original languageEnglish (US)
Pages (from-to)5408-5419
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number17
DOIs
StatePublished - Sep 10 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Li, W., Li, J., Wu, Y., Rancati, F., Vallese, S., Raveglia, L., Wu, J., Hotchandani, R., Fuller, N., Cunningham, K., Morgan, P., Fish, S., Krykbaev, R., Xu, X., Tam, S., Goldman, S. J., Abraham, W., Williams, C., Sypek, J., & Mansour, T. S. (2009). Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma. Journal of Medicinal Chemistry, 52(17), 5408-5419. https://doi.org/10.1021/jm900809r