Sphingosine 1-phosphate (S1P) is
the endogenous ligand for the
sphingosine 1-phosphate receptors (S1P<sub>1–5</sub>) and evokes
a variety of cellular responses through their stimulation. The interaction
of S1P with the S1P receptors plays a fundamental physiological role
in a number of processes including vascular development and stabilization,
lymphocyte migration, and proliferation. Agonism of S1P<sub>1</sub>, in particular, has been shown to play a significant role in lymphocyte
trafficking from the thymus and secondary lymphoid organs, resulting
in immunosuppression. This article will detail the discovery and SAR
of a potent and selective series of isoxazole based full agonists
of S1P<sub>1</sub>. Isoxazole <b>6d</b> demonstrated impressive
efficacy when administered orally in a rat model of arthritis and
in a mouse experimental autoimmune encephalomyelitis (EAE) model of
multiple sclerosis
