Synthesis, biological evaluation and molecular modeling of GW 501516 analogues.
Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPARδ and a moderate agonist against PPARα. Docking of compound 2e into PPARδ revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473.
Department of Pharmaceutical Chemistry, University of Oslo, Norway.
Calin C
CC
Ciocoiu
Aina W
AW
Ravna
Ingebrigt
I
Sylte
Trond Vidar
TV
Hansen
D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D019301:Oleic Acid / Q000378:metabolism*; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry*
C425931:GW 501516; D047494:PPAR delta; D013844:Thiazoles; D019301:Oleic Acid