PMID: 9427656Mar 7, 1998Paper

Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library

Chemistry & Biology
P J BrownT M Willson

Abstract

The peroxisome proliferator-activated receptors (PPARs) were cloned as orphan members of the nuclear receptor superfamily of transcription factors. The identification of subtype-selective ligands for PPARalpha and PPARgamma has led to the discovery of their roles in the regulation of lipid metabolism and glucose homeostasis. No subtype-selective PPARdelta ligands are available and the function of this subtype is currently unknown. A three-component library was designed in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chemical diversity. Synthesis and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pools with the highest activity on PPARdelta led to the identification of GW 2433 as the first high-affinity PPARdelta ligand. [3H]GW 2433 is an effective radioligand for use in PPARdelta competition-binding assays. The synthesis of biased chemical libraries is an efficient approach to the identification of lead molecules for members of sequence-related receptor families. This approach is well suited to the discovery of small-molecule ligands for orphan receptors.

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Citations

Dec 5, 2003·Molecular Genetics and Metabolism·Heidelinde RamplerJohannes Berger
Apr 13, 2001·European Journal of Pharmacology·G FerryJ A Boutin
Dec 28, 1999·Bioorganic & Medicinal Chemistry Letters·B R HenkeT M Willson
May 29, 2000·The Proceedings of the Nutrition Society·R UauyC Rojas
Jan 30, 2007·PPAR Research·Z Elizabeth FloydJeffrey M Gimble
Jun 20, 2013·Mediators of Inflammation·Francisco A MonsalveRodrigo Moore-Carrasco
Nov 23, 2000·Proceedings of the National Academy of Sciences of the United States of America·R A GuptaR N DuBois
Apr 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·W R OliverT M Willson
Feb 23, 2008·Bioorganic & Medicinal Chemistry Letters·Wei WangPeter T W Cheng
Nov 22, 2007·Bioorganic & Medicinal Chemistry Letters·Jay M MatthewsKeith T Demarest
Aug 30, 2008·Bioorganic & Medicinal Chemistry Letters·Barry G ShearerTimothy M Willson
Oct 26, 1999·Endocrine Reviews·V Giguère
Oct 26, 1999·Endocrine Reviews·B Desvergne, W Wahli
Nov 30, 2006·Pharmacological Reviews·Liliane MichalikWalter Wahli
Nov 24, 1999·Current Opinion in Clinical Nutrition and Metabolic Care·J P Pégorier
Aug 24, 1999·Current Opinion in Clinical Nutrition and Metabolic Care·L Gelman, J Auwerx
Jan 31, 2002·Annual Review of Medicine·Joel Berger, David E Moller
Nov 13, 1998·The Journal of Biological Chemistry·J UppenbergA Berkenstam
Aug 10, 2000·Medicinal Research Reviews·K W Buchan, D G Hassall
Feb 26, 2000·Journal of Medicinal Chemistry·T M WillsonB R Henke

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