On the Metabolically Active Form of Metaglidasen: Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator-Activated Receptors and Skeletal Muscles.

Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor ? (PPAR?), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen? s metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPAR? and PPAR? subtypes. As expected, both showed partial agonist activity toward PPAR?; the investigation of PPAR? activity, however, led to unexpected results. In particular,(S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPAR? were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects ...