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PPARa/c binding and functional activation in vitro,
thereby providing a class of molecules with the opportuni-
ty to potentially fine-tune the insulin sensitizing and lipid-
loweringeffects. Theenantioselectivesynthesisandinvivo
studies with pure (S) antipodes will be reported
separately.
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Acknowledgments
The authors gratefully acknowledge Christian Bitsch,
Stefan Burli, Thomas Burger, Caroline Prassler, and
¨
Ernst Schaffter for chemical syntheses, Angele Flament
and Astride Schnoebelen for in vitro testing, as well as
Bernard Gsell and Martine Stihle for protein prepara-
tion and crystals.
References and notes
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29. Racemates are described only. Selected compounds have
been prepared in optically pure form and it has been
confirmed that essentially all PPAR activity is residing in
the (S) enantiomers. Synthesis and in vivo activity of
further developed optically pure compounds will be
reported separately.
30. Binggeli, A.; Wirz, B.; Grether, U.; Hilpert, H.; Humm,
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31. Effects are reported in relation to reference compounds
whose activity was set to 100%: 2-(S)-2-(2-Benzoyl-phe-
nylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-eth-
oxy]-phenyl}-propionic acid (Farglitazar, GW 262570)
(PPAR alpha); 5-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-
ethoxy]-benzo[b]thiophen-7-ylmethyl}-thiazolidine-2,4-dione
(Edaglitazone) (PPAR gamma); and {2-methyl-4-[4-meth-
yl-2(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-
phenoxy}-acetic acid (GW 501516) (PPAR delta).
32. Co-crystals of PPARc-LBD with 13 were obtained using
an identical protocol as described in Burgermeister, E.
et al. Mol. Endocrinol. 2006, 20, 809. Data have been
˚
collected in-house on a rotating anode (k = 1.5418 A) to a
˚
maximum resolution of 2.1 A. Crystals belong to the
orthorhombic space group P212121 with cell axes a = 54.3,
˚
b = 68.3, and c = 87.9 A. For structure determination, the
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data have been refined against an existing in-house
PPARc-LBD structure. Difference electron density was
used to place the ligand by real space refinement.
33. The coordinates of the PPARc-compound 13 structure
were deposited to the Protein Data Bank (PDBid:
2gtk).
15. Hyun, K. H.; Lee, D. Y.; Lee, B.-S.; Kim, C. K. QSAR
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