Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists. (1st January 2020)

• Record Type: Journal Article
• Authors: Hurtevent, Aurélie; Le Naour, Morgan; Leclerc, Veronique; Carato, Pascal; Melnyk, Patricia; Hennuyer, Nathalie; Staels, Bart; Beucher-Gaudin, Monique; Caignard, Daniel-Henri; Dacquet, Catherine; Lebegue, Nicolas
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 524
• Page End: 538
• Publication Date: 2020-01-01
• Subjects: Type 2 diabetes -- PPAR -- SPPARγM -- benzothiazol-2-one -- body weight gain; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2020.1713771
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 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 tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the ( S )-stereoisomer 44 b displaying the best in vitro pharmacological profile. Compound 44 b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44 b 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 and could be considered as a selective PPARγ modulator (SPPARγM).