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Vol. 301, Issue 2, 747-752, May 2002

Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule alpha 4beta 1 Antagonists

E. Kudlacz, C. Whitney, C. Andresen, A. Duplantier, G. Beckius, L. Chupak, A. Klein, K. Kraus and A. Milici

Pfizer Global Research and Development, Groton, Connecticut

Inhibition of alpha 4beta 1/vascular cell adhesion molecule-1 (VCAM-1) interactions have therapeutic potential in treating allergic airway disease because of the importance of these adhesion molecules in the trafficking of eosinophils, lymphocytes, and monocytes. We examined several small molecule inhibitors of alpha 4beta 1/VCAM-1 interactions with in vitro potencies (IC50 values) ranging from 0.52 nM (CP-664511; 3-[3-(1-{2-[3-methoxy-4-(3-O-tolyl-ureido)phenyl]-acetylamino}-3-methyl-butyl)isoxazol-5-yl]-propionic acid) to 38.5 nM (CP-609643; 3-[3-methyl-1-{2-[4-(3-O-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid). The same compounds were evaluated in vivo using a murine model of ovalbumin-induced pulmonary eosinophilia. In this model, systemic administration of antibodies against alpha 4 reduced bronchoalveolar lavage (BAL) eosinophilia ~60%. Small molecule alpha 4beta 1 antagonists were administered by intratracheal instillation and demonstrated dose-dependent inhibition of BAL eosinophil numbers and achieved a maximum inhibition of ~60%. In general, the rank order of potency for these compounds in vitro was consistent with that observed in vivo, which confirms that their efficacy is likely via blockade of alpha 4beta 1/VCAM-1 interactions. The most potent compound, CP-664511, also inhibited BAL eosinophilia following s.c. administration (1-10 mg/kg, s.c.). These data support the utility of small molecule alpha 4beta 1 antagonists in the treatment of relevant diseases, such as asthma.

0022-3565/02/3012-0747$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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