Discovery of a novel class of zwitterionic, potent, selective and orally active S1P1 direct agonists

Amido-1,3,4-thiadiazoles were identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype-1 agonists. Starting from a micromolar HTS compound we developed a robust structural–activity relationship, to get to a lead that demonstrated good selectivity and excellent in vivo potency in rat models. Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural–activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.