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

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. (C) 2014 Elsevier Ltd. All rights reserved.