Novel 5-nitropyrimidine derivatives bearing endo-azabicyclic alcohols/amines as potent GPR119 agonists

Bioorg Med Chem. 2017 Jan 1;25(1):254-260. doi: 10.1016/j.bmc.2016.10.030. Epub 2016 Oct 27.

Abstract

A series of GPR119 agonists based on a 5-nitropyrimidine scaffold bearing endo-azabicyclic substituents were synthesized and evaluated for their GPR119 agonistic activities. Most compounds exhibited much stronger EC50 values than that of oleoylethanolamide (OEA). Among them, derivatives from endo-azabicyclic alcohols displayed more potent GPR119 agonistic activities than compounds with endo-azabicyclic amines. Especially the optimized compounds (6, 7, 8, 12, 17) were shown to have potent biological activities and were identified as full agonists. Isopropyl carbamate compound 8 synthesized from endo-azabicyclic alcohol was observed to have the best EC50 value (0.6nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity.

Keywords: 5-Nitropyrimidine; Full agonists; GPR119 agonists; endo-Azabicyclic alcohol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HEK293 Cells
  • Humans
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Sulfones / chemical synthesis
  • Sulfones / pharmacology*
  • Tropanes / chemical synthesis
  • Tropanes / pharmacology*

Substances

  • GPR119 protein, human
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • Sulfones
  • Tropanes
  • isopropyl 3-(6-(2-fluoro-4-(methylsulfonyl)phenylamino)-5-nitropyrimidin-4-yloxy)-8-azabicyclo(3.2.1)octane-8-carboxylate