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).
Highlights
Type 2 diabetes (T2D), is a metabolic disorder characterized by hyperglycemia caused by impaired insulin secretion from the pancreas and by the increased insulin resistance of peripheral tissues [1,2]
Melting points were determined on a BÜCHI B-540 apparatus and are uncorrected
The condensation reaction between benzoyl heterocycles and racemic ethoxy propionic acid esters 17a,b was classically carried out in the presence of potassium carbonate in DMF at 90 °C, and the desired acids 31-38 were obtained after lithium hydroxide mediated saponification (Scheme 3)
Summary
Type 2 diabetes (T2D), is a metabolic disorder characterized by hyperglycemia caused by impaired insulin secretion from the pancreas and by the increased insulin resistance of peripheral tissues [1,2]. INT131 was designed as a selective PPAR modulator (SPPAR M) to maintain the benefits of the PPAR full agonists while reducing or deleting their undesirable side effects [12, 13] This selective PPAR modulator (SPPAR M) and others [14] had partial agonist activity and showed increased insulin sensitivity and robust glucose-lowering activity with a reduction of the adverse effects observed with PPAR full agonists, whatever the animal model of diabetes. These results illustrated that anti-diabetic effects of PPAR ligands can be decoupled from unwanted side effects as oedema or weight gain
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