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profile. At concentrations up to 10 lM most analogs
reported did not show any activation of other PPAR
subtypes or other nuclear receptors. An in vitro meta-
bolic stability assessment of compounds 1 and 23 gave
no metabolic liabilities after incubation with mouse,
rat or human liver microsomes. Additionally, com-
pounds 1 and 23 had favorable pharmacokinetic proper-
ties (F > 50%, Cmax > 4 lM, t1/2 ꢀ 3–6 h) when dosed
orally at 10 mpk as a 0.5% CMC suspension in mice.
We believe that the compounds described will be highly
valuable tools to dissect pharmacological effects of selec-
tive PPARd activation in animal models.
14. Wei, Z.-L.; Kozikowski, A. P. J. Org. Chem. 2003, 68,
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Acknowledgments
17. Adams, A. D.; Yuen, W.; Hu, Z.; Santini, C.; Jones, A. B.;
MacNaul, K. L.; Berger, J. P.; Doebber, T. W.; Moller, D.
E. Bioorg. Med. Chem. Lett. 2003, 13, 931.
18. Weigand, S.; Bischoff, H.; Dittrich-Wengenroth, E.;
Heckroth, H.; Lang, D.; Vaupel, A.; Woltering, M.
Bioorg. Med. Chem. Lett. 2005, 15, 4619.
We gratefully acknowledge Drs. John Wityak, Don
Karanewsky, Martin Seidel, T. R. Vedananda, Sandra
Teixeira, and Peter G. Schultz for their helpful discus-
sions and support.
19. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Parks, D. J.;
Blanchard, S. G.; Brown, P. J.; Sternbach, D. D.;
Lehmann, J. M.; Wisely, G. B.; Willson, T. M.; Kliewer,
S. A.; Milburn, M. V. Mol. Cell 1999, 3, 397.
Supplementary data
20. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Plunket, K. D.;
Moore, L. B.; Collins, J. L.; Oplinger, J. A.; Kliewer, S. A.;
Gampe, R. T., Jr.; McKee, D. D.; Moore, J. T.; Willson, T.
M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 13919.
Supplementary data associated with this article can
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and pG5-Luc using Fugene6 for 6 h, then treated with
compounds diluted to
a
1· final concentration in
1%DMSO for 18–20 h at 37 ꢁC, after which time the cells
were lysed with Britelite (Perkin Elmer, Cat. #6016979)
and the plates were read on the CLIPR (Molecular
Devices, Sunnyvale CA).
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