Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists

In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.

Graphical abstractIn pursuit of potent and selective sphingosine-1-phosphate receptor agonists, further SAR expansion on our previously reported scaffolds led to discovery of novel series of molecules with excellent in vitro and in vivo potency in both mouse and rat models.Figure optionsDownload full-size imageDownload as PowerPoint slide