Synthesis and biological evaluation of pyrimidine derivatives with diverse azabicyclic ether/amine as novel GPR119 agonist

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2515-2519. doi: 10.1016/j.bmcl.2017.03.092. Epub 2017 Apr 2.

Abstract

A class of novel pyrimidine derivatives bearing diverse conformationally restricted azabicyclic ether/amine were designed, synthesized and evaluated for their GPR119 agonist activities against type 2 diabetes. Most compounds exhibited superior hEC50 values to endogenous lipid oleoylethanolamide (OEA). Analogs with 2-fluoro substitution in the aryl ring showed more potent GPR119 activation than those without fluorine. Especially compound 27m synthesized from endo-azabicyclic alcohol was observed to have the best EC50 value (1.2nM) and quite good agonistic activity (112.2% max) as a full agonist.

Keywords: Full agonist; GPR119 agonist; Pyrimidine derivatives; Type 2 diabetes; endo-Azabicyclic ether/amine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry*
  • Ethers / chemistry*
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*
  • Structure-Activity Relationship

Substances

  • Amines
  • Ethers
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Pyrimidines
  • Receptors, G-Protein-Coupled