C. Parmenon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1617–1622
1621
Table 1. Activity of compounds in cell-based transactivation assay
against human PPAR
References and notes
a
1. Saltiel, A. R. Cell 2001, 104, 517.
Compound
Binding PPARc
Ki (nM)
Transactivation EC50
(nM) (% activity)b
2. Zimmet, P. Z.; Alberti, K. G. M. M.; Shaw, J. Nature
2001, 414, 782.
3. Moller, D. E. Nature 2001, 414, 821.
hPPARa
hPPARc
Rosiglitazone
Tesaglitazar
8
18
10,000 (15)
414 (89)
Na
4 (100)
37 (76)
4. Isseman, I.; Green, S. Nature 1990, 347, 645.
5. Desvergne, B.; Wahli, W. Endocr. Rev. 1999, 20, 649.
6. Berger, J. P.; Akiyama, T. E.; Meinke, P. T. Trends
Pharmacol. Sci. 2005, 26, 244.
8
10,000
10,000
618
152 (140)
195 (74)
48 (100)
19 (113)
14 (185)
11 (167)
14 (185)
65 (107)
7.85 (95)
9
Na
29
30
31
34
35
36
(S)-37
189 (33)
30 (45)
29 (66)
12 (53)
29 (66)
194 (52)
114 (63)
7. Reifel Miller, A. Drug Dev. Res. 2006, 67, 574.
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Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.;
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Harrity, T.; Ma, Z.; Moore, L.; Ren, J.; Seethala, R.;
Cheng, L.; Sleph, P.; Sun, W.; Tieman, A.; Wetterau, J.
R.; Doweyko, A.; Chandrasena, G.; Chang, S. Y.;
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Mortensen, S. B.; Anders-Svensson, L.; Rasmussen, H.
B.; Lehmann, S. V.; Polivka, Z.; Sindelar, K.; Panajotova,
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079719, 2006.
10,000
10,000
48
>10,000
89
18
a Values are means of three experiments (na, not active).
b Refer to maximal activity obtained with each compound expressed in
percentage of maximal activity of Rosiglitazone at 10À6 M for
PPARc and of WY 14,64317 at 10À5 M for PPARa.
It is noteworthy that no correlation between EC50 values
obtained from transactivation PPARc tests and Ki val-
ues from binding tests, could suggest that these deriva-
tives have
Rosiglitazone binding site.
a
binding site different from the
The partial PPARc gene reporter response of compound
9 (74%) suggests a different capacity for this derivative
to induce recruitment on the co-activator/co-repressor
on PPARc, as compared to those observed with Rosig-
litazone. Complementary experiments, especially in vivo
assay, are ongoing to study with more precision, the im-
pact of these new partial PPARc agonist compounds in
animal model of type-2 diabetes and metabolic syn-
drome, mainly in terms of anti-diabetic properties and
potential side effects like edema formation and weight
gain.
11. Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J. Org.
Chem. 1981, 46, 5214.
12. (a) Li, W. R.; Ewing, W. R.; Harris, B. D.; Jouillie, M.
´
J. Am. Chem. Soc. 1990, 112, 7659; (b) Shin, I.; Lee, M.;
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D. J. Org. Chem. 2001, 66, 7303; (d) Scherkenbeck, J.;
The 4,4-dimethyl-1,2,3,4-tetrahydroquinoline-based com-
pounds are effective PPARc selective agonists and
dual-acting agonists of PPARa and PPARc. Their phar-
macological profiles translate very well into activity in
human cells in vitro in terms of transactivation.
Plant, A.; Stieber, F.; Losel, P.; Dyker, H. Bioorg. Med.
¨
Chem. Lett. 2002, 12, 1625; (e) Bischofberger, N.; Wald-
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Finally, structural variations of the lead derivatives 9
(as PPARc partial agonist) and 37 (as PPARa/c dual
agonist) are under investigations. That way we wish to
modulate activity especially toward more potent
PPARc partial agonist with potentially PPARa resid-
ual agonist.
13. Aikins, J. A.; Haurez, M.; Rizzo, J.; Van Hoeck, J. P.;
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`
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Acknowledgments
This work was supported by the French Ministry of Re-
search and Technology and by Servier Industry: ACI
‘Molecules and Therapeutics Targets’. We also thank
Sandrine Zubrzycki (Institut de Chimie Organique et
Analytique, Orleans) for capillary electrophoresis
analysis.
15. Fused-silica capillary column, 70 cm · 50 lm, applied
voltage, À15 kV, buffer 100 mM of phosphoric acid
(EtOH) 3 N, pH 3.0, 5 mM. b-Cyclodextrin SBE and
15 mM. b-Cyclodextrin trimethyl, detection at 214 nm,
temperature 25 ꢁC, concentration 200 ppm.