Aza-bicyclic amino acid sulfonamides as α4β 14β7 integrin antagonists

Alexey B. Dyatkin, William J. Hoekstra, William A. Kinney, Maria Kontoyianni, Rosemary J. Santulli, Edward S. Kimball, M. Carolyn Fisher, Stephen M. Prouty, William M. Abraham, Patricia Andrade-Gordon, Dennis J. Hlasta, Wei He, Pamela J. Hornby, Bruce P. Damiano, Bruce E. Maryanoff

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12 Scopus citations

Abstract

The design, synthesis, and biological activity of novel α 4β1 and α4β7 integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent α 4β1-selective and dual α4β 14β7 antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.

Original languageEnglish
Pages (from-to)591-596
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number3
DOIs
StatePublished - Feb 9 2004
Externally publishedYes

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ASJC Scopus subject areas

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

Cite this

Dyatkin, A. B., Hoekstra, W. J., Kinney, W. A., Kontoyianni, M., Santulli, R. J., Kimball, E. S., Fisher, M. C., Prouty, S. M., Abraham, W. M., Andrade-Gordon, P., Hlasta, D. J., He, W., Hornby, P. J., Damiano, B. P., & Maryanoff, B. E. (2004). Aza-bicyclic amino acid sulfonamides as α4β 14β7 integrin antagonists. Bioorganic and Medicinal Chemistry Letters, 14(3), 591-596. https://doi.org/10.1016/j.bmcl.2003.11.063