Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: Discovery of potent S1P1 receptor agonists

The novel immunosuppressant FTY720 has been demonstrated to elicit immunomodulating effects via interaction with the G-protein coupled receptor S1P1. FTY720 induced agonism at the S1P3 receptor, however, has been shown to result in mild bradycardia, a minor side-effect of initial FTY720 therapy. This report describes the synthesis of several potent 4(5)-phenylimidazole-based S1P1 receptor agonists that are accompanied by poor agonist activity at S1P3. For instance, compound 20 displayed an EC50 = 4.7 ± 1.3 nM at the S1P1 receptor and EC50 = 780 ± 1.3 nM at the S1P3 receptor using a [γ-35S]GTP-binding assay as compared to phospho-FTY720 (S1P1: EC50 = 1.3 ± 1.3 nM, S1P3: EC50 = 2.0 ± 2.4 nM).