Design And Synthesis Of S1P Receptor Agonists

Transplantation as an indispensable and effective method of treating losing function of human apparatus had made great progress in the past fifty years. However, transplantation rejection becomes the bottle-neck of further developing of transplant at present, so it is very important to develop immunosuppressant drugs with potent effect and lower toxicity. The agitating of sphingosine 1-phosphate receptors (S1PRs) not only drives T lymphocytes into PLNs via a chemokine dependent mechanism, but also prevents their egress from the PLNs. This reorientation of T lymphocytes can inhibit the ingress of T cells into the allografts, but do not impair the immune memory of T cell, and also do not influence the number and function of Ag-activated T cells. So S1PR agonists treated as a new class of immunosuppressants have their particular advantages. Therefore, discovery of novel SIPRs agonists is significant to the development of transplant.The analysis of the structure-activity relationship of S1P receptor agonists suggests that S1PR agonists usually include three parts:polar head, linker, hydrophobic chain, and the activity of S-isomers is better than that of R-isomers. Based on this SAR, we design the target compounds which have amino alcohol as polar head and different group as hydrophobic area, including four different series of target compounds:(S)-2-amino-3-(4-acylphenyl)propan-l-ols, (S)-2-amino-3-(4-alkylphenyl)propan-l-ols, (S)-2-amino-3-(4-substituted benzyloxy)propan-l-ols, (S)-2-amino-3-(4-substituted phenoxyacetphenyl)propan-l-ols. Nineteen compounds were synthesized according to four different procedures, and were confirmed by 1H-NMR and MS. At the same time, the synthesis of positive drug (FTY720) was improved. FTY-720 was synthesized via 7 steps using benzyl chloride and 1-bromo-heptane as the starting materials and total yield was 22.5%.Biological evaluation of target compounds is under study.