title: On the metabolically active form of metaglidasen: improved synthesis and investigation of its peculiar activity on peroxisome proliferator-activated receptors and skeletal muscles.
abstract: Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα 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 PPARγ 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.
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", 70126 Bari (Italy).
authors: Antonio
authors: A
authors: Laghezza
authors: Roberta
authors: R
authors: Montanari
authors: Antonio
authors: A
authors: Lavecchia
authors: Luca
authors: L
authors: Piemontese
authors: Giorgio
authors: G
authors: Pochetti
authors: Vito
authors: V
authors: Iacobazzi
authors: Vittoria
authors: V
authors: Infantino
authors: Davide
authors: D
authors: Capelli
authors: Michela
authors: M
authors: De Bellis
authors: Antonella
authors: A
authors: Liantonio
authors: Sabata
authors: S
authors: Pierno
authors: Paolo
authors: P
authors: Tortorella
authors: Diana
authors: D
authors: Conte Camerino
authors: Fulvio
authors: F
authors: Loiodice
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D062105:Molecular Docking Simulation; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma
keywords: PPAR modulators; X-ray crystallography; molecular recognition; receptors