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

  • J Med Chem. 2009 Sep 10;52(17):5408-19. doi: 10.1021/jm900809r.
Wei Li  1 ,  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
Affiliations
  • 1. Chemical Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. [email protected]
PMID: 19725580 DOI: 10.1021/jm900809r
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.

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