Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
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Sauerberg P, Olsen GS, Jeppesen L, Mogensen JP, Pettersson I, Jeppesen CB, Daugaard JR, Galsgaard ED, Ynddal L, Fleckner J, Panajotova V, Polivka Z, Pihera P, Havranek M, Wulff EM
Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
J Med Chem. 2007 Apr 5;50(7):1495-503. Epub 2007 Mar 8.
- PubMed ID
- 17343371 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cardarine Peroxisome proliferator-activated receptor alpha EC 50 (nM) 3900 N/A N/A Details Cardarine Peroxisome proliferator-activated receptor delta EC 50 (nM) 7.9 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor alpha EC 50 (nM) >10000 N/A N/A Details Rosiglitazone Peroxisome proliferator-activated receptor gamma EC 50 (nM) 310 N/A N/A Details