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

Abstract

Meriem Chayah,1– 3 Angélica Luque-González,1 Verónica Gómez-Pérez,1 Diego Salagre,4,5 Amjad Al-Shdaifat,6 Joaquín María Campos,1,2 Ana Conejo-García,1,2 Ahmad Agil2,4,5 1Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Granada, Spain; 2Biosanitary Institute of Granada (Ibs.granada), SAS-University of Granada, Granada, Spain; 3Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government (GENYO), Granada, Spain; 4Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain; 5Federico Oloriz Neuroscience Institute, University of Granada, Granada, Spain; 6Department of Medicine and Family Medicine, Faculty of Medicine, Hashemite University, Zarqa, JordaniaCorrespondence: Ahmad Agil; Ana Conejo-García, Email [email protected]; [email protected]: 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 (Compound 1-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: diabetes mellitus type 2, DPP-4 inhibitors, purine derivatives, ZDF rats

Keywords

• diabetes mellitus type 2
• dpp-4 inhibitors
• purine derivatives
• zdf rats