1 research outputs found
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 S1P<sub>1</sub> receptors, while
a variety of side effects have been ascribed to its S1P<sub>3</sub> 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 S1P<sub>1</sub> receptor agonism. Here we describe a study of the tolerance of the
S1P<sub>1</sub> and S1P<sub>3</sub> 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 S1P<sub>1</sub> receptor agonists with good selectivity
vs S1P<sub>3</sub> receptors, efficacy at <1 mg/kg oral doses,
and developability properties suitable for progression into preclinical
development