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

• Published in: European journal of medicinal chemistry Vol. 137; pp. 310 - 326
• Main Authors: Pirat, Celine, Dacquet, Catherine, Leclerc, Veronique, Hennuyer, Nathalie, Beucher-Gaudin, Monique, Zanirato, Ghislaine, Géant, Anne, Staels, Bart, Ktorza, Alain, Farce, Amaury, Caignard, Daniel-Henri, Berthelot, Pascal, Lebegue, Nicolas
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 08.09.2017; Elsevier
• Subjects: Animals; Body Weight - drug effects; Body-weight gain; Caloric Restriction; Calorie restriction; Cells, Cultured; Cercopithecus aethiops; Chemistry, Medicinal; COS Cells; Diabetes; Dose-Response Relationship, Drug; Gene Expression Profiling; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - genetics; Life Sciences & Biomedicine; Ligands; Male; Mice; Mice, Obese; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; PPAR; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Resveratrol; Science & Technology; SGK1; SIRT1; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - metabolism; Structure-Activity Relationship; PPAR; Body-weight gain; Calorie restriction; Resveratrol; Diabetes; SGK1; SIRT1; METABOLITES; PROLIFERATOR-ACTIVATED RECEPTORS; VALIDATION; POTENT; INSULIN-RESISTANCE; PPAR-GAMMA; COMPLICATIONS; UP-REGULATION; CELL
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.006

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. The synthesis of benzothiazol-2-one containing α-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds along with their in vitro and in vivo anti-diabetic activities is reported. [Display omitted] •A series of fused PPARγ agonist ligands and SIRT1-activating compounds were synthesized.•Compound 14d showed high anti-diabetic efficacy in an ob/ob mice model.•Compound 14d limited side effects by SIRT1 enzymatic activation and SGK1 expression inhibition.