Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

Bioorg Med Chem Lett. 2018 Oct 15;28(19):3255-3259. doi: 10.1016/j.bmcl.2018.07.044. Epub 2018 Jul 30.

Abstract

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.

Keywords: Plasma stability; Psoriasis; S1PR1; Soft-drug; Topical.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Aryldialkylphosphatase / blood
  • Chromatography, High Pressure Liquid
  • Chromatography, Reverse-Phase
  • Drug Discovery*
  • Esterases / blood
  • Esterases / metabolism
  • Humans
  • Receptors, Lysosphingolipid / drug effects*
  • Skin / enzymology
  • Solubility
  • Sphingosine-1-Phosphate Receptors
  • Structure-Activity Relationship
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*

Substances

  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors
  • Thiazoles
  • ponesimod
  • Esterases
  • Aryldialkylphosphatase