Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma.
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 SJ, Abraham W, Williams C, Sypek J, Mansour TS.
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.