Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists for the Treatment of Type 2 Diabetes

Journal of Medicinal Chemistry
2004.0

Abstract

Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, insulin resistance, and lipid abnormalities. Peroxisome proliferator-activated receptors (PPARs) α and γ play key roles in regulating lipid metabolism and insulin sensitivity: PPARα agonists (fibrates) improve dyslipidemia but have side effects, while PPARγ agonists (glitazones) enhance insulin sensitivity but cause weight gain and edema. Thus, developing PPARα/γ dual agonists that combine the benefits of both subtypes is a logical approach. This miniperspective reviews the progress in PPARα/γ dual agonists, including their structural designs, in vitro potencies (binding and transactivation assays), in vivo efficacy in animal models, clinical development status, structural studies on ligand-PPAR interactions, and the challenges in optimizing the balance of PPARα/γ activity to maximize efficacy and minimize side effects for type 2 diabetes treatment.

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