Sphingosine-1-phosphate is a biologically active sphingolipid, which is involved in the regulation of various physiological functions as well as pathophysiological processes. The concentration of S1P is relatively high in blood but extremely low in tissue interstitium, and an S1P concentration gradient promotes the egress of lymphocytes from secondary lymphoid tissue into the bloodstream. Fingolimod is a nonselective S1P receptor agonist approved by the United States Food and Drug Administration in 2010 as the first oral treatment for relapsing forms of MS. Sphingosine kinase phosphorylates fingolimod in vivo, which then acts as an agonist of four of the five S1P receptors. Fingolimod exerts its immunomodulatory effect, at least in part, by inducing internalization of S1P1 on lymphocytes, which reduces the responsiveness of these cells to the S1P gradient and inhibits egress of lymphocytes from secondary lymphoid tissue. In addition, fingolimod exerts direct effects on S1P receptors expressed on CNS cells, such as S1P1 on astrocytes and S1P5 on oligodendrocytes. In clinical trials, fingolimod treatment was beneficial for patients with MS, and the annualized relapse rate in patients receiving fingolimod was significantly lower than in the patients receiving interferon b-1a, which is an established treatment for relapsing-remitting MS. However, a pooled analysis of two phase 3 studies demonstrated that 6.1% of patients receiving 0.5 mg fingolimod and 11.0% of patients receiving 1.25 mg fingolimod experienced bradycardia after the first dose. Heart rate reduction peaked at 4– 5 h after dosing, and the mean heart rate decreased by 8 and 11 beats per minute at nadir with 0.5 and 1.25 mg, respectively. Further, a reduction in the mean forced expiratory volume in 1 second was observed. The average reduction from baseline in the percentage of predicted FEV1 at month 6 was 8.8% and 2.8% in the patients receiving 5.0 mg and 1.25 mg fingolimod, respectively, as compared with 1.9% in the placebo group. Preclinical data suggest that some of the adverse effects of fingolimod are caused by its interaction with S1P3. We therefore assumed that S1P receptor agonists that do not engage S1P3 might provide a better therapeutic option for lymphocytemediated disease with fewer adverse effects than nonselective S1P receptor agonists such as fingolimod. To address this question, we developed ASP4058 as a novel S1P receptor agonist selective for S1P1 and S1P5. Here we present the in vitro profile of ASP4058, its in vivo effect on peripheral lymphocytes, and its efficacy in MK-1775 experimental autoimmune encephalomyelitis, which is a widely used animal model of MS. We also investigated the effect of ASP4058 on the heart rate and pulmonary function of rats compared with fingolimod. Here we determined the preclinical profiles of ASP4058, a novel S1P1, S1P5 agonist synthesized by Astellas Pharma Inc.