Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
Sznaidman
Marcos L
ML
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
Haffner
Curt D
CD
Maloney
Patrick R
PR
Fivush
Adam
A
Chao
Esther
E
Goreham
Donna
D
Sierra
Michael L
ML
LeGrumelec
Christelle
C
Xu
H Eric
HE
Montana
Valerie G
VG
Lambert
Millard H
MH
Willson
Timothy M
TM
Oliver
William R
WR
Sternbach
Daniel D
DD
D000818:Animals; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D051379:Mice; D011869:Radioligand Assay; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists*; D015533:Transcriptional Activation; D010636:Phenols; D013438:Sulfhydryl Compounds
D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; C425931:GW 501516; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds