Peroxisome proliferator-activated receptor agonists and antagonists: a patent review (2014-present)

ABSTRACT

Introduction: Peroxisome proliferator-activated receptors (PPARs), PPARα, PPARδ, and PPARγ, play an important role in the regulation of various physiological processes, specifically lipid and energy metabolism and immunity. PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism but PPARδ-acting drugs are not yet available. Many synthetic ligands for PPARs have been developed to expand their therapeutic applications.

Areas covered: The authors searched recent patent activity regarding PPAR ligands. Novel PPARα agonists, PPARδ agonists, PPARγ agonists, PPARα/γ dual agonists, and PPARγ antagonists have been claimed for the treatment of metabolic disease and inflammatory disease. Methods for the combination of PPAR ligands with other drugs and expanded application of PPAR agonists for bone and neurological disease have been also claimed.

Expert opinion: Novel PPAR ligands and the combination of PPAR ligands with other drugs have been claimed for the treatment of mitochondrial disease, inflammatory/autoimmune disease, neurological disease, and cancer in addition to metabolic diseases including dyslipidemia and type 2 diabetes. Selective therapeutic actions of PPAR ligands should be exploited to avoid adverse effects. More basic studies are needed to elucidate the molecular mechanisms of selective actions.

KEYWORDS:

• Adverse effects
• metabolic disease
• inflammation
• skeletal disease
• neurological disease
• nuclear receptors
• function-selective ligands

Article highlights

• PPARα, PPARδ, and PPARγ are ligand-dependent transcription factors of the nuclear receptor superfamily that regulate lipid and energy metabolism and immunity.

• Only several fibrates (PPARα agonists) and TZDs (PPARγ agonists) are in clinical use for the treatment of hypertriglyceridemia and type 2 diabetes.

• Novel PPARα and PPARδ agonist patents have been claimed to enhance therapeutic potency in the treatment of metabolic disease.

• Novel PPARγ ligands that have less adverse effects will expand therapeutic application to bone and immunologic diseases.

• Novel PPAR ligands with/without other drugs will be useful to decrease adverse effects and to expand to new therapeutic areas such as to neurological disease.

This box summarizes the key points contained in the article.

Acknowledgments

The authors thank Dr. Andrew I Shulman for editorial assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by research budget from Nihon University School of Medicine.