2 research outputs found
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)
Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P<sub>1</sub>) Employing Ligand-Based Drug Design
Fingolimod (<b>1</b>) is the
first approved oral therapy
for the treatment of relapsing remitting multiple sclerosis. While
the phosphorylated metabolite of fingolimod was found to be a nonselective
S1P receptor agonist, agonism specifically of S1P<sub>1</sub> is responsible
for the peripheral blood lymphopenia believed to be key to its efficacy.
Identification of modulators that maintain activity on S1P<sub>1</sub> while sparing activity on other S1P receptors could offer equivalent
efficacy with reduced liabilities. We disclose in this paper a ligand-based
drug design approach that led to the discovery of a series of potent
tricyclic agonists of S1P<sub>1</sub> with selectivity over S1P<sub>3</sub> and were efficacious in a pharmacodynamic model of suppression
of circulating lymphocytes. Compound <b>10</b> had the desired
pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated
maximal efficacy when administered orally in a rat adjuvant arthritis
model