Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily whose physiological functions are linked to metabolism, energy homeostasis, cellular development, and differentiation
The characteristics of human PPARα, β/δ, and γ are well-reviewed [3,4,5] and will not be elaborated. Owing to their crucial metabolic regulatory roles and excellent druggability, many PPAR agonists have been synthesized for the treatment of metabolic diseases, especially dyslipidemia and type 2 diabetes mellitus (T2DM)
Based on a meta-analysis, pioglitazone was associated with a significant reduction of Psoriasis Area and Severity Index compared to placebo, but such an improvement was not observed in the rosiglitazone-treated cohort [274]
Summary
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily whose physiological functions are linked to metabolism, energy homeostasis, cellular development, and differentiation. The characteristics of human PPARα, β/δ, and γ are well-reviewed [3,4,5] and will not be elaborated Owing to their crucial metabolic regulatory roles and excellent druggability, many PPAR agonists have been synthesized for the treatment of metabolic diseases, especially dyslipidemia and type 2 diabetes mellitus (T2DM). The clinical success of fibrates and TZDs have propelled the development of various PPARα or γ agonists and sparked the creation of novel PPAR modulators including selective PPARβ/δ activators, dual-PPAR agonists, and pan-PPAR agonists [2]. Since the lipid-lowering activity of PPARα agonists and insulin-sensitizing effect of PPARγ agonists are extremely well-established and have been widely exploited to improve dyslipidemia and T2DM [9,10,11,12], these aspects will be excluded from this review. This review will provide a comprehensive and up-to-date overview of the latest development of PPAR modulators for the treatment of various diseases based on existing clinical data
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