Synthesis and SAR studies of a novel class of S1P1 receptor antagonists.

Abstract A series of Sodium 4-[(4-butoxyphenyl)thio]-2′-substituted-1,1′-biphenyl-3- sulfonates were identified as functional sphingosine-1-phosphate (S1P) antagonists with selectivity for the S1P 1 receptor subtype starting from chemical lead 2 , which was found while screening our in-house compound library. We performed chemical modifications on each regional structure of compound 2 , for example, on the three ring compartments, the benzyl substituents, and the long alkyl chain part. The introduction of a biphenyl skeletal structure and the installation of a hydroxyl group onto the terminal carbon in the side-chain region resulted in the potent derivative 35c , which showed >500-fold more potent S1P 1 inhibitory activity than lead compound 2 . We report herein the synthesis and structure–activity relationships of structurally novel S1P 1 receptor antagonists.