1 research outputs found
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