Author/Authors :
Alexey B. Dyatkin، نويسنده , , Yong Gong، نويسنده , , Tamara A. Miskowski، نويسنده , , Edward S. Kimball، نويسنده , , Stephen M. Prouty، نويسنده , , M. Carolyn Fisher، نويسنده , , Rosemary J. Santulli، نويسنده , , Craig R. Schneider، نويسنده , , Nathaniel H. Wallace، نويسنده , , Pamela J. Hornby، نويسنده , , Craig Diamond، نويسنده , , William A. Kinney، نويسنده , , Bruce E. Maryanoff، نويسنده , , Bruce P. Damiano، نويسنده , , Wei He، نويسنده ,
Abstract :
A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of α4β1-VCAM-1 and α4β7-MAdCAM-1 interactions. Potency and α4β1/α4β7 selectivity were sensitive to the substituent R1–R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced α4β1/α4β7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.
Keywords :
VLA-4 , VCAM-1 , Crohn’s disease , Inflammatory bowel disease , Asthma , Multiple Sclerosis , Rheumatoid arthritis , N-Acylphenylalanine , Leukocy , MAdCAM-1 , ?4?1 integrin , ?4?7 integrin
