title: Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.
abstract: A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
authors.affiliation: Discovery Medicinal Chemistry, Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, United States. karen.a.evans@gsk.com
authors.forename: Karen A
authors.initials: KA
authors.lastname: Evans
authors.forename: Barry G
authors.initials: BG
authors.lastname: Shearer
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.forename: Dongchuan
authors.initials: D
authors.lastname: Shi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Sparks
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Sternbach
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Winegar
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Christy
authors.initials: C
authors.lastname: Britt
authors.forename: James M
authors.initials: JM
authors.lastname: Way
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Epperly
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Merrihew
authors.forename: Robert X
authors.initials: RX
authors.lastname: Xu
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D047494:PPAR delta; C415326:phenoxyacetic acid