Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.

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Ciocoiu CC, Ravna AW, Sylte I, Rustan AC, Hansen TV

Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.

Bioorg Med Chem. 2011 Dec 1;19(23):6982-8. doi: 10.1016/j.bmc.2011.10.020. Epub 2011 Oct 17.

PubMed ID
22051054 [ View in PubMed
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Abstract

(+/-)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-y l)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 PPARalpha and PPARdelta, 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 PPARalpha/delta agonist with a 10-fold higher potency against the PPARdelta receptor than against the PPARalpha receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARdelta receptor with similar binding energies.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CardarinePeroxisome proliferator-activated receptor alphaEC 50 (nM)>1000N/AN/ADetails
CardarinePeroxisome proliferator-activated receptor deltaEC 50 (nM)2.9N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor alphaEC 50 (nM)>1000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor deltaEC 50 (nM)>1000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)48N/AN/ADetails