Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4281-5. doi: 10.1016/j.bmcl.2014.07.020. Epub 2014 Jul 28.

Abstract

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Keywords: Diabetes; GPR119; Thienopyrimidine; Treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Blood Glucose / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Glucose Tolerance Test
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Conformation
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • GPR119 protein, human
  • Insulin
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • thienopyrimidine