Author/Authors :
Petr Vachal، نويسنده , , Leslie M. Toth، نويسنده , , Jeffrey J. Hale، نويسنده , , Lin Yan، نويسنده , , Sander G. Mills، نويسنده , , Gary L. Chrebet، نويسنده , , Carol A. Koehane، نويسنده , , Richard Hajdu، نويسنده , , James A. Milligan، نويسنده , , Mark J. Rosenbach، نويسنده , , Suzanne Mandala، نويسنده ,
Abstract :
Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4 > 10,000-fold, S1P1/S1P5 > 600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.
Keywords :
agonist , S1P , Immunosuppressant , Heteropentalene , Lymphocyte-lowering , sphingosine-1-phosphate
