S1P 1 activation maintains endothelial barrier integrity, whereas its desensitization induces lymphopenia. SAR247799, a new G protein‐biased S1P 1 agonist, was compared to clinical stage S1P 1 ‐desensitizing compounds using a label‐free impedance assay assessing endothelial barrier integrity. SAR247799 had the highest activation‐to‐desensitization ratio (114), compared to ponesimod (7.66), ozanimod (6.35), and siponimod (0.170) and thus demonstrated the best ability to cause sustained S1P 1 activation.