Optimization of Sphingosine-1-phosphate‑1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P₁ receptors, while a variety of side effects have been ascribed to its S1P₃ receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P₁ receptor agonism. Here we describe a study of the tolerance of the S1P₁ and S1P₃ receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in <i>in vitro</i> and <i>in vivo</i> pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P₁ receptor agonists with good selectivity vs S1P₃ receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development