Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Inhibition of α4β1/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 α4β1/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 α4 reduced bronchoalveolar lavage (BAL) eosinophilia ∼60%. Small molecule α4β1 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 α4β1/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 α4β1 antagonists in the treatment of relevant diseases, such as asthma.