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

Peter J. Brown, Tracey A. Smith-Oliver, Paul S. Charifson, Nicholas C. O. Tomkinson, Adam M. Fivush, Daniel D. Sternbach, Laura E. Wade, Lisa Orband-Miller, Derek J. Parks, Steven G. Blanchard

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metab. and glucose homeostasis. No subtype-selective PPARδ 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 chem. 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 PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [3H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chem. libraries is an efficient approach to the identification of lead mols. for members of sequence-related receptor families. This approach is well suited to the discovery of small-mol. ligands for orphan receptors.
Original languageUndefined/Unknown
Pages (from-to)909-918
Number of pages10
JournalChemistry and Biology
Volume4
Issue number12
DOIs
Publication statusPublished - 1997

Keywords

  • receptor ligands
  • ligands
  • peroxisome
  • nuclear receptor

Cite this

Brown, P. J., Smith-Oliver, T. A., Charifson, P. S., Tomkinson, N. C. O., Fivush, A. M., Sternbach, D. D., ... Blanchard, S. G. (1997). Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chemistry and Biology, 4(12), 909-918. https://doi.org/10.1016/S1074-5521(97)90299-4
Brown, Peter J. ; Smith-Oliver, Tracey A. ; Charifson, Paul S. ; Tomkinson, Nicholas C. O. ; Fivush, Adam M. ; Sternbach, Daniel D. ; Wade, Laura E. ; Orband-Miller, Lisa ; Parks, Derek J. ; Blanchard, Steven G. / Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. In: Chemistry and Biology. 1997 ; Vol. 4, No. 12. pp. 909-918.
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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 PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metab. and glucose homeostasis. No subtype-selective PPARδ 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 chem. 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 PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [3H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chem. libraries is an efficient approach to the identification of lead mols. for members of sequence-related receptor families. This approach is well suited to the discovery of small-mol. ligands for orphan receptors.",
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Brown, PJ, Smith-Oliver, TA, Charifson, PS, Tomkinson, NCO, Fivush, AM, Sternbach, DD, Wade, LE, Orband-Miller, L, Parks, DJ & Blanchard, SG 1997, 'Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library', Chemistry and Biology, vol. 4, no. 12, pp. 909-918. https://doi.org/10.1016/S1074-5521(97)90299-4

Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. / Brown, Peter J.; Smith-Oliver, Tracey A.; Charifson, Paul S.; Tomkinson, Nicholas C. O.; Fivush, Adam M.; Sternbach, Daniel D.; Wade, Laura E.; Orband-Miller, Lisa; Parks, Derek J.; Blanchard, Steven G.

In: Chemistry and Biology, Vol. 4, No. 12, 1997, p. 909-918.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library

AU - Brown, Peter J.

AU - Smith-Oliver, Tracey A.

AU - Charifson, Paul S.

AU - Tomkinson, Nicholas C. O.

AU - Fivush, Adam M.

AU - Sternbach, Daniel D.

AU - Wade, Laura E.

AU - Orband-Miller, Lisa

AU - Parks, Derek J.

AU - Blanchard, Steven G.

PY - 1997

Y1 - 1997

N2 - 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 PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metab. and glucose homeostasis. No subtype-selective PPARδ 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 chem. 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 PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [3H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chem. libraries is an efficient approach to the identification of lead mols. for members of sequence-related receptor families. This approach is well suited to the discovery of small-mol. ligands for orphan receptors.

AB - 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 PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metab. and glucose homeostasis. No subtype-selective PPARδ 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 chem. 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 PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [3H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chem. libraries is an efficient approach to the identification of lead mols. for members of sequence-related receptor families. This approach is well suited to the discovery of small-mol. ligands for orphan receptors.

KW - receptor ligands

KW - ligands

KW - peroxisome

KW - nuclear receptor

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M3 - Article

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SP - 909

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JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 1074-5521

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