Discovery of Novel 1,2,4-ThiadiazoleDerivatives asPotent, Orally Active Agonists of Sphingosine 1-Phosphate ReceptorSubtype 1 (S1P1).

A novel series of 1,2,4-thiadiazole compounds was discoveredasselective S1P1agonists. The extensive structure–activityrelationship studies for these analogues were reported. Among them, 17gwas identified to show high in vitro potency with reasonablefree unbound fraction in plasma (Fu>0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokineticproperties in mouse and rat. Oral administration of 1 mg/kg 17gresulted in significant peripheral lymphocytes reductionat 4 h after dose and rapid lymphocytes recovery at 24 h. 17gshowed a transient lymphopenia profile in the repeated dose studyin mouse. In addition, 17galso demonstrated efficacycomparable to that of FTY720 (1) in the mouse EAE modelof MS. [ABSTRACT FROM AUTHOR]