Structure–activity relationship studies of S1P agonists with a dihydronaphthalene scaffold

Structure–activity relationship of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker was identified. Structure–activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P3 and in vivo PLL activity in mice.