Pharmacological peroxisome proliferator-activated receptorγ ligands: emerging clinical indications beyond diabetes

Abstract

The discovery of peroxisome proliferator-activated receptor γ (PPARγ) as the molecular target for antidiabetic thiazolidinediones has heralded a new era in the approach to understanding the pathophysiology of insulin resistance and its relationship to cardiovascular disease. However, the subsequent discovery of PPARγ-dependent modulation of immune function and the cell cycle has led to a new paradigm in the approach to treating proliferative, inflammatory diseases. Moreover, PPARγ agonists can promote apoptosis, block angiogenesis and inhibit pathological remodelling in a variety of malignant and non-malignant pathological states. These findings imply that the pharmacological modulation of this key nuclear transcription factor and its co-factors could be important tools in understanding the relationships between multigenic diseases, and pave the way to a focused interventional approach in their treatment. With the availability of the PPARγ protein crystal structure, the ligand binding domain co-ordinates and a better knowledge of the interaction of PPARγ with co-factor assemblies, libraries of simple synthetic organic PPARγ ligands can be constructed. High throughput screening can identify the best candidates for targeting cellular phenotypic transition, cell cycle control, inflammation and apoptosis. Instead of single agents for single pathologies, one can envisage the development of multifunctional therapeutic agents that target the multiple cellular processes that contribute to multifactorial diseases such as diabetes, hypertension, atherosclerosis, psoriasis and other inflammatory diseases, and carcinogenesis. The considerable potential of PPARγ ligands in the treatment of diseases other than diabetes is the subject of this review.

• angiogenesis and neovascularisation
• apoptosis
• atherosclerosis
• common cancers
• growth arrest and differentiation
• hypertension
• inflammation
• inflammatory bowel disease
• insulin resistance
• peroxisome proliferator-activated receptor-γ
• proliferation
• psoriasis
• retinal degeneration
• thiazolidinediones
• transcription-modulating drugs
• vascular restenosis