Sphingosine-1-phosphate (S1P) is the endogenous ligand for the sphingosine-1-phosphate G-protein coupled receptors (S1P1-5).  The interaction of S1P with the S1P receptors plays a fundamental physiological role in many processes including vascular stabilization, heart development, lymphocyte homing, and cancer angiogenesis.  Agonism of S1P1, in particular, has been shown to block lymphocyte trafficking from the thymus and secondary lymph nodes resulting in immunosuppression.  As a result, agonists of this type hold promise as therapeutics for autoimmune disorders.  This presentation will outline the identification and synthesis of a potent and selective series of direct-acting agonists of S1P1 based on an ethanolamine template.  Compounds in this series demonstrated efficacy when administered orally in a rat model of arthritis as well as in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

Discovery and SAR of a novel series of ethanolamine-based direct-acting agonists of sphingosine-1-phosphate 1 (S1P1)

245th National Meeting (2013)

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