Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats

Drug Des Devel Ther. 2024 Apr 10:18:1133-1141. doi: 10.2147/DDDT.S450917. eCollection 2024.


Type 2 diabetes mellitus (T2DM) is one of the world's principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure (1) has been developed and tested in vitro and in vivo in Zücker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 µM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.

Keywords: DPP-4 inhibitors; ZDF rats; diabetes mellitus type 2; purine derivatives.

MeSH terms

  • Animals
  • Antiviral Agents
  • Bronchodilator Agents
  • Diabetes Mellitus, Type 2* / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
  • Glucagon-Like Peptide 1
  • Hyperglycemia*
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Obesity / drug therapy
  • Protease Inhibitors
  • Rats
  • Rats, Zucker
  • Vasodilator Agents
  • Vildagliptin / pharmacology
  • Vildagliptin / therapeutic use


  • Antiviral Agents
  • Bronchodilator Agents
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucagon-Like Peptide 1
  • Hypoglycemic Agents
  • Protease Inhibitors
  • Vasodilator Agents
  • Vildagliptin

Grants and funding

This research was supported by the Spanish Ministry of Science and Innovation through (grants PID2021.128109OB.I00 and PID2021-125900OB-I00) by European Regional Development Fund (ERDF) as a way of making Europe.