Author/Authors :
Edward C. Lawson، نويسنده , , Rosemary J. Santulli، نويسنده , , Alexey B. Dyatkin، نويسنده , , Scott A. Ballentine، نويسنده , , William M. Abraham، نويسنده , , Sandra Rudman، نويسنده , , Clive P. Page، نويسنده , , Lawrence de Garavilla، نويسنده , , Bruce P. Damiano، نويسنده , , William A. Kinney، نويسنده , , Bruce E. Maryanoff، نويسنده ,
Abstract :
The α4β1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent α4β1 antagonists that we evaluated for safety and efficacy, 1 was selected as a lead candidate for anti-asthma therapy by the inhalation route. We devised an optimized stereoselective synthesis to facilitate the preparation of a sufficiently large quantity of 1 for assessment in vivo. Administration of 1 to allergen-sensitive sheep by inhalation blocked the late-phase response of asthma and abolished airway hyper-responsiveness at 24 h following the antigen challenge. Additionally, the recruitment of inflammatory cells into the lungs was inhibited. Administration of 1 to ovalbumin-sensitized guinea pigs intraperitoneally blocked airway resistance and inhibited the recruitment of inflammatory cells.
