Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists

• Main Authors: Aurélie Hurtevent, Morgan Le Naour, Veronique Leclerc, Pascal Carato, Patricia Melnyk, Nathalie Hennuyer, Bart Staels, Monique Beucher-Gaudin, Daniel-Henri Caignard, Catherine Dacquet, Nicolas Lebegue
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: type 2 diabetes; ppar; spparγm; benzothiazol-2-one; body weight gain
• Online Access: http://dx.doi.org/10.1080/14756366.2020.1713771
• ISSN: 1475-6366; 1475-6374

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).