New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease.

Abstract

INTRODUCTION:

Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects.

AREAS COVERED:

This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

EXPERT OPINION:

ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

• Authors: Amirhossein Sahebkar, Gerard T Chew, Gerald F Watts
• Journal: Expert opinion on pharmacotherapy (Expert Opin Pharmacother) Vol. 15 Issue 4 Pg. 493-503 (Mar 2014) ISSN: 1744-7666 [Electronic] England
• PMID: 24428677 (Publication Type: Journal Article, Review)

Chemical References

• (2-methyl-4-(5-methyl-2-(4-trifluoromethyl-phenyl)-2H-(1,2,3)triazol-4-ylmethylsulfanyl)phenoxy)acetic acid
• 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid
• 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid
• Acetates
• Chalcones
• Cholesterol, HDL
• GW 501516
• INT 131
• Lipoproteins, HDL
• Peroxisome Proliferator-Activated Receptors
• Propionates
• Quinolines
• Sulfonamides
• Thiazoles
• Triazoles
• Triglycerides
• Fenofibrate

Topics

• Acetates (therapeutic use)
• Animals
• Atherosclerosis (prevention & control)
• Chalcones (therapeutic use)
• Cholesterol, HDL (blood)
• Dyslipidemias (drug therapy, metabolism)
• Fatty Liver (drug therapy, metabolism)
• Fenofibrate (analogs & derivatives, therapeutic use)
• Humans
• Insulin Resistance
• Lipoproteins, HDL (blood)
• Non-alcoholic Fatty Liver Disease
• Peroxisome Proliferator-Activated Receptors (agonists, metabolism)
• Propionates (therapeutic use)
• Quinolines (therapeutic use)
• Sulfonamides (therapeutic use)
• Thiazoles (therapeutic use)
• Triazoles (therapeutic use)
• Triglycerides (blood)