Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists

Discovery of two potent and selective sphingosine-1-phosphate receptor agonist chemotypes, alkoxy-phenylamide and alkoxy-phenylimidazole, with potent in vivo oral activity in mouse. In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 ( 4b) and PPI-4691 ( 10a), demonstrated dose responsive lymphopenia, when administered orally.