Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as GPR119 agonist for treatment of type 2 diabetes

Bioorg Med Chem. 2018 Aug 7;26(14):4080-4087. doi: 10.1016/j.bmc.2018.06.035. Epub 2018 Jun 28.

Abstract

We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0-2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0-2h at the dose of 300 mg/kg.

Keywords: GPR119 agonist; Pyrimido[5,4-d]pyrimidine; Type 2 diabetes; oGTT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology*
  • CHO Cells
  • Cricetulus
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glucose Tolerance Test
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

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