The front cover picture shows the develop
ment of the inverse PPARβ/δ agonist
methyl 3-(
m>Nm>-(2-(2-ethoxyethoxy)-4-(hexyla
mino)phenyl)sulfa
moyl)thiophene-2-carboxylate (PT-S264,
9u, shown centered). Inspired by the X-structure of the fatty acid eicosapentaenoic acid in co
mplex with the PPARβ/δ ligand-binding do
main, we envisioned that Y-shaped ligands (orange Y) would
most likely better
mi
mic the binding cleft, thus leading to a series of co
mpounds displaying increased potency. To opti
mize the solubility of the co
mpounds with respect to assay conditions, the introduction of an additional oxygen (orange O) in the newly incorporated side chain finally led to
9u, one of the
most potent inverse PPARβ/δ agonists described so far. Further
more,
9u displayed prolonged cellular activity and,
moreover, biologically relevant plas
ma concentrations in
mice could be achieved. More infor
mation can be found in the Full Paper by Wibke E. Diederich et al. on
page 488 in Issue 5, 2016 (DOI:
mdc.201500594" rel="references:http://dx.doi.org/10.1002/cmdc.201500594">10.1002/cmdc.201500594).