Discovery of Novel 1,2,4-Thiadiazole Derivatives as Potent, Orally Active Agonists of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P₁)

A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P₁ agonists. The extensive structure–activity relationship studies for these analogues were reported. Among them, <b>17g</b> was identified to show high in vitro potency with reasonable free unbound fraction in plasma (<i>F</i>_u > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg <b>17g</b> resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. <b>17g</b> showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, <b>17g</b> also demonstrated efficacy comparable to that of FTY720 (<b>1</b>) in the mouse EAE model of MS