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

Edward C. Lawson, Rosemary J. Santulli, Alexey B. Dyatkin, Scott A. Ballentine, William M. Abraham, Sandra Rudman, Clive P. Page, Lawrence de Garavilla, Bruce P. Damiano, William A. Kinney, Bruce E. Maryanoff

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4208-4216
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number12
StatePublished - Jun 15 2006


  • Antagonist
  • Integrin
  • VLA-4

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science


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