title: Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
authors.forename: Marcos L
authors.initials: ML
authors.lastname: Sznaidman
authors.forename: Curt D
authors.initials: CD
authors.lastname: Haffner
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Maloney
authors.forename: Adam
authors.initials: A
authors.lastname: Fivush
authors.forename: Esther
authors.initials: E
authors.lastname: Chao
authors.forename: Donna
authors.initials: D
authors.lastname: Goreham
authors.forename: Michael L
authors.initials: ML
authors.lastname: Sierra
authors.forename: Christelle
authors.initials: C
authors.lastname: LeGrumelec
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Montana
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: William R
authors.initials: WR
authors.lastname: Oliver
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Sternbach
mesh_terms: 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
chemical_list: 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