Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists

Abstract We report herein the synthesis and structure–activity relationships (SAR) of a series of benzyl ether compounds as an S1P 1 receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P 1 and S1P 3 agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P 1 /S1P 3 selectivity. These changes of the S1P 1 and S1P 3 agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P 1 X-ray crystal structure and S1P 3 homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P 1 /S1P 3 selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.