A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition

A new series of analogues or derivatives of the previously
reported
PPARα/γ dual agonist LT175 allowed the identification
of ligand 10, which was able to potently activate both
PPARα and -γ subtypes as full and partial agonists, respectively.
Docking studies were performed to provide a molecular explanation
for this different behavior on the two different targets. In vivo
experiments showed that this compound induced a significant reduction
in blood glucose and lipid levels in an STZ-induced diabetic mouse
model displaying no toxic effects on bone, kidney, and liver. By examining
in depth the antihyperglycemic activity of 10, we found
out that it produced a slight but significant inhibition of the mitochondrial
pyruvate carrier, acting also through insulin-independent mechanisms.
This is the first example of a PPARα/γ dual agonist reported
to show this inhibitory effect representing, therefore, the potential
lead of a new class of drugs for treatment of dyslipidemic type 2
diabetes.