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tylamine (12), 2-phenethylamine (13) or 3-phenylpropylamine
References and notes
(14) had marginal impact on potency and decreased activation
down to 75–80%.
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Molecular docking studies suggest that substitution by a larger
substituent in
a-position of the carboxylic acid head group might
cause a distinct binding manner of the ligand (Fig. 1). Comparison
of the PPARc ligand binding domain co-crystallized with farglitazar
(PDB ID: 1fm9)25 and a partial agonist (PDB ID: 3b3k)29 reveals a
conformational change of F282 (Fig. 1, right side).30,29 We therefore
expected that an elongation of the naphthyl group might reduce
the maximal activation of PPARc. The para-position of the naph-
thalene residue seemed to be suitable for the introduction of a
bulky substituent that would possibly cause a conformational
change of F282. Introducing a phenyl residue in para-position of
the naphthalene actually led to a subtype-selective PPARc modula-
tor (15) with a transactivation of 45% and an EC50 of 4.5 lM
(Table 1).
Scheme 2 shows the synthesis of compound 15, which was
done by bromination of 1-naphthylacetic acid in para-position of
the naphthalene using bromine in glacial acetic acid (i). The next
step (ii) was a Suzuki-coupling with phenylboronic acid and tetra-
kis(triphenylphosphine)-palladium(0) in a mixture of dioxane and
water. It was followed by an esterification (iii) using thionyl chlo-
ride and ethanol. The bromination in
a-position of the carboxylic
acid head group was done with NBS (N-bromosuccinimide) and
benzoyl peroxide in carbon tetrachloride (iv). The subsequent reac-
tions were done as in case of the other compounds.
In this study we have demonstrated that the variation of the a-
position of the carboxylic acid head group of pirinixic acid has an
impact not only on PPAR subtype selectivity, but also on maximally
achievable activity. Through this effect we obtained several sub-
type-selective PPAR
range. By insertion of a phenyl residue in para-position of the
naphthalene moiety we obtained a subtype-selective PPAR mod-
c agonists with EC50 values in low micromolar
c
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c
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Acknowledgments
We gratefully acknowledge financial support from the Frankfurt
International Research Graduate School for Translational Biomedi-
cine (FIRST), the Else-Kroener-Fresenius-Stiftung Bad Homburg
and Lipid Signaling Forschungszentrum Frankfurt (LiFF).
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Supplementary data
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