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Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P<sub>1</sub>)
Sphingosine-1-phosphate
(S1P) is a bioactive sphingolipid metabolite
that regulates a multitude of physiological processes such as lymphocyte
trafficking, cardiac function, vascular development, and inflammation.
Because of the ability of S1P<sub>1</sub> receptor agonists to suppress
lymphocyte egress, they have great potential as therapeutic agents
in a variety of autoimmune diseases. In this article, the discovery
of selective, direct acting S1P<sub>1</sub> agonists utilizing an
ethanolamine scaffold containing a terminal carboxylic acid is described.
Potent S1P<sub>1</sub> agonists such as compounds <b>18a</b> and <b>19a</b> which have greater than 1000-fold selectivity
over S1P<sub>3</sub> are described. These compounds efficiently reduce
blood lymphocyte counts in rats through 24 h after single doses of
1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds
are discussed. Compound <b>19a</b> was further studied in two
preclinical models of disease, exhibiting good efficacy in both the
rat adjuvant arthritis model (AA) and the mouse experimental autoimmune
encephalomyelitis model (EAE)