Anti-diabetic activity of fused PPARγ-SIRT1 ligands with limited body-weight gain by mimicking calorie restriction and decreasing SGK1 expression

Autor: Nathalie Hennuyer, Ghislaine Zanirato, Anne Géant, Catherine Dacquet, Daniel-Henri Caignard, Nicolas Lebegue, Bart Staels, Veronique Leclerc, Celine Pirat, Monique Beucher-Gaudin, Pascal Berthelot, Amaury Farce, Alain Ktorza
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
medicine.medical_treatment
Calorie restriction
Peroxisome proliferator-activated receptor
Mice
Obese
Resveratrol
Protein Serine-Threonine Kinases
Ligands
Immediate-Early Proteins
03 medical and health sciences
chemistry.chemical_compound
Mice
Structure-Activity Relationship
0302 clinical medicine
Sirtuin 1
Diabetes mellitus
Internal medicine
Drug Discovery
Chlorocebus aethiops
medicine
Animals
Hypoglycemic Agents
Cells
Cultured
Butein
Caloric Restriction
Pharmacology
chemistry.chemical_classification
Triglyceride
Dose-Response Relationship
Drug
Molecular Structure
Insulin
Gene Expression Profiling
Organic Chemistry
Body Weight
General Medicine
medicine.disease
Molecular Docking Simulation
PPAR gamma
030104 developmental biology
Endocrinology
chemistry
030220 oncology & carcinogenesis
COS Cells
SGK1
Zdroj: European journal of medicinal chemistry. 137
ISSN: 1768-3254
Popis: A series of benzothiazol-2-one containing α-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds were designed as fused full PPARγ agonist ligands and SIRT1-activating compounds for the treatment of type 2 diabetes (T2D) and its complications. Compound 14d displayed the best in vitro pharmacological profile with full PPARγ agonist activity (Emax = 98%, EC50 = 200 nM), SIRT1 enzymatic activation (+128%) and SGK1 expression inhibition (- 57%) which is known to limit side effects as fluid retention and body-weight gain. Compound 14d showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain by mimicking calorie restriction (CR) and inhibiting SGK1 expression.
Databáze: OpenAIRE
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