Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor

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, S1P(1). The optimized structure represents a highly S1P(1)-selective and efficacious agonist: S1P(1)/S1P(2), S1P(1)/S1P(3), S1P(1)/S1P(4) > 10,000-fold, S1P(1)/S1P(5) > 600-fold, while EC50 (S1P(1)) < 0.2 nM. In vivo experiments are consistent with S1P(1) receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect. (c) 2006 Elsevier Ltd. All rights reserved.