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


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 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.


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.
Brown
P J
PJ
Department of Medicinal Chemistry, Glaxo Wellcome Research & Development, PO Box 13398, 5 Moore Drive, Research Triangle Park, NC 27709-3398, USA. pjb5890@glaxowellcome.com
Smith-Oliver
T A
TA
Charifson
P S
PS
Tomkinson
N C
NC
Fivush
A M
AM
Sternbach
D D
DD
Wade
L E
LE
Orband-Miller
L
L
Parks
D J
DJ
Blanchard
S G
SG
Kliewer
S A
SA
Lehmann
J M
JM
Willson
T M
TM
D001667:Binding, Competitive / Q000187:drug effects; D002087:Butyrates / Q000138:chemical synthesis*; D003001:Cloning, Molecular; D006801:Humans; D008024:Ligands; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002087:Butyrates; C110636:GW 2433; D008024:Ligands; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors