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Published ahead of print on January 31, 2003, doi:10.1164/rccm.200207-696OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 10, May 2003, 1400-1409

A more recent version of this article appeared on May 15, 2003
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Submitted on July 12, 2002
Accepted on January 24, 2003

A small molecule VLA4 antagonist can inhibit ovalbumin induced lung inflammation

Gloria C Koo1*, Kashmira Shah1, Gloria J Ding1, Jianying Xiao1, Richard Wnek1, George Doherty1, Xin Chun Tong1, R. Blake Pepinsky2, Ko-Chung Lin2, William K Hagmann1, Doug Kawka1, and Irwin I Singer1

1 Merck Research Laboratories, Merck and Co., Rahway, NJ, USA, 2 Biogen Inc., Cambridge, MA, USA

* To whom correspondence should be addressed. E-mail: gloria_koo{at}merck.com.

A non-peptidyl small molecule antagonist, compound A, to non activated VLA4 was examined in lung inflammation induced by a single dose of ovalbumin challenge. Compound A presented a good pharmacokinetic property, when given intratracheally, and the blood cells from such pharmacokinetic study showed good receptor occupancy of the compound for about 8 hours. Compound A was then tested in an ovalbumin induced airway inflammation model by intranasal or intravenous route of administration. There was a dose-dependent inhibition of eosinophilia in the bronchiolar lavage fluid, when compound A was given intranasally, but not when it was given intravenously. For comparison, anti-body to VLA4 and another compound, BIO1211, which reacts only with activated VLA4, were examined in this system. Immunohistochemical analyses of the lung tissue substantiated the findings in the bronchiolar lavage fluid. Specific staining of the major basic protein of eosinophils showed peribronchiolar infiltration of eosinophils. Some of these eosinophils were also positive for nitrotyrosine, suggesting activation of eosinophils in the lung interstitium. There was deposition of major basic protein and nitrotyrosine at the base of the perivascular endothelium, indicative of degranulation of eosinophils in the area. After intranasal treatment with compound A, eosinophils in the lungs and their activation products were substantially decreased, documenting its effectiveness in inhibiting lung inflammation.
Key words: VLA4 antagonist, asthma




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