Bruce E. Maryanoff1, Lawrence de Garavilla1, Michael N. Greco1, Barbara J. Haertlein1, Grace I. Wells1, Patricia Andrade-Gordon1 and William M. Abraham2. American Journal of Respiratory and Critical Care Medicine Vol 181. pp. 247-253, (2010). Published ahead of print on October 29, 2009
Rationale: Mast cells and neutrophils are key contributors to the pathophysiological inflammatory processes that underpin asthma and chronic obstructive pulmonary disease, partly through the release of noxious serine proteases, including cathepsin G (Cat G) and chymase. From this standpoint, a dual inhibitor of neutrophil Cat G and mast cell chymase could protect against these disease-related inflammatory responses.
Objectives: We examined the antiinflammatory pharmacology of RWJ-355871, a dual inhibitor of Cat G and chymase, in animal models of inflammation that evince pathophysiological pathways relevant to asthma and chronic obstructive pulmonary disease to determine the therapeutic potential of this compound.
Methods: In an ovalbumin (OVA)-sensitized rat model, RWJ-355871 was administered to block the mast-cell–mediated increase in paw volume caused by OVA injection. In a sheep asthma model, antigen-induced airway responses were assessed with and without aerosol treatment with RWJ-355871. In a murine tobacco-smoke model of airway inflammation, the effect of RWJ-355871 on smoke-induced neutrophilia was determined.
Measurements and Main Results: Intravenous treatment of OVA-sensitized rats with RWJ-355871 provided dose-dependent reduction in the increase in rat paw volume. In allergic sheep, aerosol pretreatment with RWJ-355871 showed dose-dependent inhibition of the antigen-induced early response, late response, and post–antigen-induced airway hyperreponsiveness. In tobacco-smoke–exposed mice, nebulized RWJ-355871 significantly reduced the smoke-induced neutrophilia from the levels observed in untreated mice.
Conclusions: The preclinical antiinflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on Cat G and/or chymase.
Key Words: asthma • mast cells • neutrophils • pulmonary disease • serine protease • tobacco smoke • enzyme inhibitor
Weblink here