Selection of a 2-azabicyclo[2.2.2]octane-based α4β1 integrin antagonist as an inhaled anti-asthmatic agent

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.

A number of potent α4β1 antagonists were evaluated for safety and efficacy, and 1 was selected as a lead candidate. The synthesis of compound 1 was optimized and scaled up, so that it could be evaluated in allergen-sensitive sheep and ovalbumin-sensitized guinea pigs. It was found to block changes in airway resistance, hyper-responsiveness, and inflammatory cell number.Figure optionsDownload as PowerPoint slide