Current Topics in Medicinal Chemistry

Allen B. Reitz
Fox Chase Chemical Diversity Center, Inc.
Doylestown, PA


PPAR Modulators and PPAR Pan Agonists for Metabolic Diseases: The Next Generation of Drugs Targeting Peroxisome Proliferator-Activated Receptors?

Author(s): P. L. Feldman, M. H. Lambert and B. R. Henke

Affiliation: Division of Medicinal Chemistry, Metabolic Diseases Centre of Excellence in Drug Discovery, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Keywords: PPAR pan agonist, PPAR modulator, SPPARM, PPARγ, metabolic disease, diabetes, coregulator


The Peroxisome Proliferator-Activated Receptors-PPARα, PPARγ, and PPARδ--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.

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Article Details

Page: [728 - 749]
Pages: 22
DOI: 10.2174/156802608784535084