Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation.
BACKGROUND
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.


OBJECTIVE
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.


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.
Maryanoff
Bruce E
BE
Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477-0076, USA. bmaryano@scripps.edu
de Garavilla
Lawrence
L
Greco
Michael N
MN
Haertlein
Barbara J
BJ
Wells
Grace I
GI
Andrade-Gordon
Patricia
P
Abraham
William M
WM
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D056649:Cathepsin G / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007275:Injections, Intravenous; D008171:Lung Diseases / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology*; D051381:Rats; D012756:Sheep; D016896:Treatment Outcome
D015415:Biomarkers; C503282:JNJ-10311795; D063065:Organophosphonates; D010880:Piperidines; D056649:Cathepsin G; D053818:Chymases