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, Steven A. Kliewer, Jürgen M. Lehmann, Timothy M. Willson

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Background: 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 metabolism and glucose homeostasis. No subtype-selective PPARδ ligands are available and the function of this subtype is currently unknown. Results: 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 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 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.

Original languageEnglish (US)
Pages (from-to)909-918
Number of pages10
JournalChemistry and Biology
Volume4
Issue number12
StatePublished - Dec 1997

Fingerprint

Small Molecule Libraries
Peroxisome Proliferator-Activated Receptors
Ligands
Libraries
Monomers
Orphan Nuclear Receptors
Molecules
Deconvolution
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Assays
Screening
Homeostasis
Transcription Factors
Glucose

Keywords

  • Combinatorial chemistry
  • Fibrate
  • Nuclear receptor
  • Orphan receptor
  • Solid phase synthesis

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Brown, P. J., Smith-Oliver, T. A., Charifson, P. S., Tomkinson, N. C. O., Fivush, A. M., Sternbach, D. D., ... Willson, T. M. (1997). Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chemistry and Biology, 4(12), 909-918.

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.; Kliewer, Steven A.; Lehmann, Jürgen M.; Willson, Timothy M.

In: Chemistry and Biology, Vol. 4, No. 12, 12.1997, p. 909-918.

Research output: Contribution to journalArticle

Brown, PJ, Smith-Oliver, TA, Charifson, PS, Tomkinson, NCO, Fivush, AM, Sternbach, DD, Wade, LE, Orband-Miller, L, Parks, DJ, Blanchard, SG, Kliewer, SA, Lehmann, JM & Willson, TM 1997, 'Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library', Chemistry and Biology, vol. 4, no. 12, pp. 909-918.
Brown PJ, Smith-Oliver TA, Charifson PS, Tomkinson NCO, Fivush AM, Sternbach DD et al. Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chemistry and Biology. 1997 Dec;4(12):909-918.
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. ; Kliewer, Steven A. ; Lehmann, Jürgen M. ; Willson, Timothy M. / 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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