Author/Authors :
Alexey B. Dyatkin، نويسنده , , William J. Hoekstra، نويسنده , , William A Kinney، نويسنده , , Maria Kontoyianni، نويسنده , , Rosemary J Santulli، نويسنده , , Edward S Kimball، نويسنده , , M Carolyn Fisher، نويسنده , , Stephen M Prouty، نويسنده , , William M Abraham، نويسنده , , Patricia Andrade-Gordon، نويسنده , , Dennis J. Hlasta، نويسنده , , Wei He، نويسنده , , Pamela J. Hornby، نويسنده , , Bruce P. Damiano، نويسنده , , Bruce E. Maryanoff، نويسنده ,
Abstract :
The design, synthesis, and biological activity of novel α4β1 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 α4β1-selective and dual α4β1/α4β7 antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma. ©2003 Elsevier Science Ltd. All rights reserved.
