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 gamma (PPAR gamma), 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 alpha and PPAR gamma subtypes. As expected, both showed partial agonist activity toward PPAR gamma; the investigation of PPAR alpha 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 gamma were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.