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Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats.
Chayah, Meriem; Luque-González, Angélica; Gómez-Pérez, Verónica; Salagre, Diego; Al-Shdaifat, Amjad; Campos, Joaquín María; Conejo-García, Ana; Agil, Ahmad.
Afiliación
  • Chayah M; Department 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.
  • Luque-González A; Biosanitary Institute of Granada (Ibs.granada), SAS-University of Granada, Granada, Spain.
  • Gómez-Pérez V; Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government (GENYO), Granada, Spain.
  • Salagre D; Department 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.
  • Al-Shdaifat A; Department 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.
  • Campos JM; Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain.
  • Conejo-García A; Federico Oloriz Neuroscience Institute, University of Granada, Granada, Spain.
  • Agil A; Department of Medicine and Family Medicine, Faculty of Medicine, Hashemite University, Zarqa, Jordania.
Drug Des Devel Ther ; 18: 1133-1141, 2024.
Article en En | MEDLINE | ID: mdl-38618281
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diabetes Mellitus Tipo 2 / Inhibidores de la Dipeptidil-Peptidasa IV / Hiperglucemia Límite: Animals Idioma: En Revista: Drug Des Devel Ther Asunto de la revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Nueva Zelanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diabetes Mellitus Tipo 2 / Inhibidores de la Dipeptidil-Peptidasa IV / Hiperglucemia Límite: Animals Idioma: En Revista: Drug Des Devel Ther Asunto de la revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Nueva Zelanda