Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists

Bioorg Chem. 2019 May:86:103-111. doi: 10.1016/j.bioorg.2019.01.032. Epub 2019 Jan 22.

Abstract

A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC50 values (0.27-1.2 μM) though they appeared to be partial agonists.

Keywords: Dihydrocyclopentapyrimidine; GPR119 agonists; Tetrahydroquinazoline; endo-N-boc-nortropane amine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology*
  • Blood Glucose / drug effects*
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Glucose Tolerance Test
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • Antihypertensive Agents
  • Blood Glucose
  • GPR119 protein, human
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • pyrimidine