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

被引：7

作者：

Pirat, Celine ^{[1
]}

Dacquet, Catherine ^{[2
]}

Leclerc, Veronique ^{[1
]}

Hennuyer, Nathalie ^{[3
]}

Beucher-Gaudin, Monique ^{[2
]}

Zanirato, Ghislaine ^{[2
]}

Geant, Anne ^{[2
]}

Staels, Bart ^{[3
]}

Ktorza, Alain ^{[2
]}

Farce, Amaury ^{[4
]}

Caignard, Daniel-Henri ^{[5
]}

Berthelot, Pascal ^{[1
]}

Lebegue, Nicolas ^{[1
]}

机构：

[1] Univ Lille, INSERM, CHU Lille, UMRS 1172,JPArc,Ctr Rech Jean Pierre AUBERT Neurs, F-59000 Lille, France

[2] Inst Rech Servier, Pole Innovat Therapeut Malad Metab, F-92150 Suresnes, France

[3] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,U1011,EGID, F-59000 Lille, France

[4] Univ Lille, INSERM, CHU Lille, U995,LIRIC, F-59000 Lille, France

[5] Inst Rech Servier, Pole Expertise Chim Therapeut, 125 Chemin Ronde, F-78390 Croissy Sur Seine, France

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 137卷

关键词：

Diabetes; PPAR; SIRT1; SGK1; Calorie restriction; Resveratrol; Body-weight gain; PROLIFERATOR-ACTIVATED RECEPTORS; PPAR-GAMMA; INSULIN-RESISTANCE; UP-REGULATION; RESVERATROL; CELL; VALIDATION; POTENT; COMPLICATIONS; METABOLITES;

D O I：

10.1016/j.ejmech.2017.06.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of benzothiazol-2-one containing alpha-ethoxyphenylpropionic acid derivatives incorporating resveratrol or butein scaffolds were designed as fused full PPAR gamma 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 PPAR gamma agonist activity (Emax = 98%, EC50 = 200 nM), SIRTI 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 SGKI expression. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：310 / 326

页数：17

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