- Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists
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A series of nitrogen heterocycles containing α–ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the
- Beucher-Gaudin, Monique,Caignard, Daniel-Henri,Carato, Pascal,Dacquet, Catherine,Hennuyer, Nathalie,Hurtevent, Aurélie,Le Naour, Morgan,Lebegue, Nicolas,Leclerc, Veronique,Melnyk, Patricia,Staels, Bart
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p. 524 - 538
(2020/01/23)
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- Anti-diabetic activity of fused PPARγ-SIRT1 ligands with limited body-weight gain by mimicking calorie restriction and decreasing SGK1 expression
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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) an
- 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
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p. 310 - 326
(2017/06/14)
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- Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity
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Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20c and 21a. Compound 20c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21a, less potent as a dual PPARα/γ activator than 20c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.
- LeNaour, Morgan,Leclerc, Veronique,Farce, Amaury,Caignard, Daniel-Henri,Hennuyer, Nathalie,Staels, Bart,Audinot-Bouchez, Valérie,Boutin, Jean-Albert,Lonchampt, Michel,Dacquet, Catherine,Ktorza, Alain,Berthelot, Pascal,Lebegue, Nicolas
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p. 2179 - 2193
(2013/03/28)
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