title: Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
abstract: The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.
authors.affiliation: Novo Nordisk A/S, Diabetes Research Unit, Novo Nordisk Park, 2760 Måløv, Denmark. psa@novonordisk.com
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
authors.forename: Grith S
authors.initials: GS
authors.lastname: Olsen
authors.forename: Lone
authors.initials: L
authors.lastname: Jeppesen
authors.forename: John P
authors.initials: JP
authors.lastname: Mogensen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pettersson
authors.forename: Claus B
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: Jens R
authors.initials: JR
authors.lastname: Daugaard
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Galsgaard
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: Vladimira
authors.initials: V
authors.lastname: Panajotova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Polivka
authors.forename: Pavel
authors.initials: P
authors.lastname: Pihera
authors.forename: Miroslav
authors.initials: M
authors.lastname: Havranek
authors.forename: Erik M
authors.initials: EM
authors.lastname: Wulff
mesh_terms: D000284:Administration, Oral; D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D018360:Crystallography, X-Ray; D004041:Dietary Fats / Q000008:administration & dosage; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000166:cytology; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists*; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: C519515:(4-(3,3-bis(4-bromophenyl)allylthio)-2-chlorophenoxy)acetic acid; D000498:Allyl Compounds; D053299:Apolipoprotein B-100; D053480:Cholesterol Ester Transfer Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D047494:PPAR delta; D010648:Phenylacetates