Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists
Résumé
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).
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Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of -alkoxyphenylpropionic acid derived PPAR agonists.pdf (900.18 Ko)
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