title: Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.
abstract: (±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies.
authors: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.
authors: Calin C
authors: CC
authors: Ciocoiu
authors: Aina W
authors: AW
authors: Ravna
authors: Ingebrigt
authors: I
authors: Sylte
authors: Arild C
authors: AC
authors: Rustan
authors: Trond Vidar
authors: TV
authors: Hansen
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D032342:Muscle Cells / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists*; D011485:Protein Binding; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C425931:GW 501516; D006845:Hydrocarbons, Fluorinated; D047493:PPAR alpha; D013844:Thiazoles