Design and synthesis of pyrazolopyridine derivatives as sphingosine 1-phosphate receptor 2 ligands

Bioorg Med Chem Lett. 2018 Feb 1;28(3):488-496. doi: 10.1016/j.bmcl.2017.12.010. Epub 2017 Dec 6.

Abstract

Eleven new sphingosine 1-phosphate receptor 2 (S1PR2) ligands were synthesized by modifying lead compound N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazine-1-carboxamide (JTE-013) and their binding affinities toward S1PRs were determined in vitro using [32P]S1P and cell membranes expressing recombinant human S1PRs. Among these ligands, 35a (IC50 = 29.1 ± 2.6 nM) and 35b (IC50 = 56.5 ± 4.0 nM) exhibit binding potency toward S1PR2 comparable to JTE-013 (IC50 = 58.4 ± 7.4 nM) with good selectivity for S1PR2 over the other S1PRs (IC50 > 1000 nM). Further optimization of these analogues may identify additional and more potent and selective compounds targeting S1PR2.

Keywords: Binding affinities; Multiple sclerosis; Selectivity; Sphingosine 1-phosphate receptor 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Ligands
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Lysosphingolipid / antagonists & inhibitors*
  • Receptors, Lysosphingolipid / metabolism
  • Recombinant Proteins / metabolism
  • Sphingosine-1-Phosphate Receptors
  • Structure-Activity Relationship

Substances

  • Ligands
  • Pyrazoles
  • Pyridines
  • Receptors, Lysosphingolipid
  • Recombinant Proteins
  • S1PR2 protein, human
  • Sphingosine-1-Phosphate Receptors
  • pyrazolopyridine