Structural and functional insights into PPAR-γ: Review of its potential and drug design innovations for the development of antidiabetic agents

Oct 22, 2025European journal of medicinal chemistry

Structure and function of PPAR-gamma and new drug ideas for diabetes treatment

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Abstract

PPAR-γ is a critical target for type 2 diabetes mellitus therapy.

Diabetes mellitus is characterized by persistent high blood sugar due to metabolic dysregulation.
PPAR-γ plays a key role in managing fat storage, blood sugar levels, and fat metabolism.
Therapeutic agents targeting PPAR-γ, such as TZDs and selective modulators, show varying efficacy in diabetes treatment.
Mutations in PPAR-γ can lead to drug resistance, complicating treatment options.
Recent advancements in synthetic PPAR-γ agonists demonstrate potential antidiabetic effects.
The review emphasizes design strategies for developing next-generation PPAR-γ agonists.

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Diabetes mellitus (DM) is a lasting metabolic condition characterized by persistent hyperglycemia caused by dysregulation of carbohydrate, fats and protein metabolism. PPAR-γ, a nuclear receptor regulating adipogenesis, glucose homeostasis, and lipid metabolism, has emerged as a critical target for type 2 diabetes mellitus (T2DM) therapy. This review covers the structural framework, activation mechanism, physiological functions, and its role in metabolic disorders. The therapeutic potential of PPAR-γ agonists, including TZDs, dual and pan-PPAR-modulators, and selective PPAR-γ modulators, is further discussed with emphasis on clinical evidence and comparative efficacy with other metabolic targets. This review particularly discusses the drug resistance caused due to PPAR-γ mutations and highlights the PPAR-γ modulatory potential of naturally occurring ligands. The discussion includes the advancements in the design of synthetic PPAR-γ agonists reported to have antidiabetic activity in the last five years, along with recent structure-activity relationship (SAR) trends. This compilation provides a focused framework aimed at guiding the rational design strategies necessary for advancing development of PPAR-γ agonists. Overall, this review will serve as a valuable resource for medicinal chemists and researchers to develop next-generation antidiabetic agents targeting PPAR-γ.

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Structural and functional insights into PPAR-γ: Review of its potential and drug design innovations for the development of antidiabetic agents

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