Selection of a 2-azabicyclo[2.2.2]octane-based alpha4beta1 integrin antagonist as an inhaled anti-asthmatic agent

Bioorg Med Chem. 2006 Jun 15;14(12):4208-16. doi: 10.1016/j.bmc.2006.01.067. Epub 2006 Feb 21.


The alpha4beta1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent alpha4beta1 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 24h 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.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Anti-Asthmatic Agents / administration & dosage*
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / pharmacology*
  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Cell Adhesion / drug effects
  • Cell Line
  • Drug Administration Schedule
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Injections, Intraperitoneal
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Male
  • Molecular Conformation
  • Ovalbumin / antagonists & inhibitors
  • Ovalbumin / pharmacology
  • Respiratory Function Tests
  • Respiratory System / drug effects
  • Respiratory System / physiopathology
  • Sheep
  • Structure-Activity Relationship


  • Anti-Asthmatic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Integrin alpha4beta1
  • Ovalbumin