6724 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
Chart 1. ERRγ Agonist Acyl Hydrazone 1
Brief Articles
(4) Horard, B.; Vanacker, J. M. Estrogen receptor-related receptors: orphan
receptors desperately seeking a ligand. J. Mol. Endocrinol. 2003, 31,
349–357.
(5) Hentschke, M.; Susens, U.; Borgmeyer, U. PGC-1 and PERC,
coactivators of the estrogen receptor-related receptor gamma. Biochem.
Biophys. Res. Commun. 2002, 299, 872–879.
(6) Huss, J. M.; Kopp, R. P.; Kelly, D. P. Peroxisome proliferator-activated
receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-
enriched nuclear receptors estrogen-related receptor-alpha and -gamma.
Identification of novel leucine-rich interaction motif within PGC-
1alpha. J. Biol. Chem. 2002, 277, 40265–40274.
Chart 2. ERRR Inverse Agonist Indole 4 and ERR Antagonist/
ERRγ Inverse Agonist 5 (4-OHT)
(7) Kamei, Y.; Ohizumi, H.; Fujitani, Y.; Nemoto, T.; Tanaka, T.;
Takahashi, N.; Kawada, T.; Miyoshi, M.; Ezaki, O.; Kakizuka, A.
PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand,
whose expression induces a high-energy expenditure and antagonizes
obesity. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 12378–12383.
(8) Debevec, D.; Christian, M.; Morganstein, D.; Seth, A.; Herzog, B.;
Parker, M.; White, R. Receptor interacting protein 140 regulates
expression of uncoupling protein 1 in adipocytes through specific
peroxisome proliferator activated receptor isoforms and estrogen-
related receptor alpha. Mol. Endocrinol. 2007, 21, 1581–1592.
(9) Kallen, J.; Schlaeppi, J. M.; Bitsch, F.; Filipuzzi, I.; Schilb, A.; Riou,
V.; Graham, A.; Strauss, A.; Geiser, M.; Fournier, B. Evidence for
ligand-independent transcriptional activation of the human estrogen-
related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand
binding domain in complex with peroxisome proliferator-activated
receptor coactivator-1alpha. J. Biol. Chem. 2004, 279, 49330–49337.
(10) Busch, B. B.; Stevens, W. C., Jr.; Martin, R.; Ordentlich, P.; Zhou,
S.; Sapp, D. W.; Horlick, R. A.; Mohan, R. Identification of a selective
inverse agonist for the orphan nuclear receptor estrogen-related receptor
alpha. J. Med. Chem. 2004, 47, 5593–5596.
(11) Kallen, J.; Lattmann, R.; Beerli, R.; Blechschmidt, A.; Blommers,
M. J.; Geiser, M.; Ottl, J.; Schlaeppi, J. M.; Strauss, A.; Fournier, B.
Crystal structure of human estrogen-related receptor alpha in complex
with a synthetic inverse agonist reveals its novel molecular mechanism.
J. Biol. Chem. 2007, 282, 23231–23239.
(12) Zuercher, W. J.; Gaillard, S.; Orband-Miller, L. A.; Chao, E. Y.;
Shearer, B. G.; Jones, D. G.; Miller, A. B.; Collins, J. L.; McDonnell,
D. P.; Willson, T. M. Identification and structure-activity relationship
of phenolic acyl hydrazones as selective agonists for the estrogen-
related orphan nuclear receptors ERRbeta and ERRgamma. J. Med.
Chem. 2005, 48, 3107–3109.
(13) Wang, L.; Zuercher, W. J.; Consler, T. G.; Lambert, M. H.; Miller,
A. B.; Orband-Miller, L. A.; McKee, D. D.; Willson, T. M.; Nolte,
R. T. X-ray crystal structures of the estrogen-related receptor-gamma
ligand binding domain in three functional states reveal the molecular
basis of small molecule regulation. J. Biol. Chem. 2006, 281, 37773–
37781.
(14) Nolte, R. T.; Wang, L.; Orband-Miller, L. A.; Way, J. M.; Martin,
J. J.; Roa, A. M.; Vela, L.; Miller, A. B.; Willson, T. M.; Zuercher,
W. J. Identification and X-ray Crystal Structure of an ERR-alpha
Inverse Agonist Reveals a New Mechanism of Nuclear Receptor
Antagonism. Abstracts of Papers, 230th National Meeting of the
American Chemical Society, Washington, DC, Aug 28 through Sep
1, 2005; American Chemical Society: Washington, DC, 2005; MEDI-
474.
(15) Suetsugi, M.; Su, L.; Karlsberg, K.; Yuan, Y. C.; Chen, S. Flavone
and isoflavone phytoestrogens are agonists of estrogen-related recep-
tors. Mol. Cancer Res. 2003, 1, 981–991.
(16) Coward, P.; Lee, D.; Hull, M. V.; Lehmann, J. M. 4-Hydroxytamoxifen
binds to and deactivates the estrogen-related receptor gamma. Proc.
Natl. Acad. Sci. U.S.A. 2001, 98, 8880–8884.
mixture was stirred at 80 °C for 30 min. The volatiles were then
removed under reduced pressure, and isobutylamine (1 mmol) and
Et3N (1 mmol) in CH2Cl2 (2 mL) were added. The mixture was
allowed to stir at room temperature overnight, after which time
amide formation and acetate cleavage were checked for completion.
After removal of volatiles and dissolution in MeOH, the phenolic
1
amide product 3h was purified by reverse-phase HPLC. H NMR
(DMSO-d6) δ 0.84 (d, J ) 6.7 Hz, 6H), 1.79 (m, 1H), 3.01 (m,
2H), 6.76 (d, J ) 8.8 Hz, 2H), 7.68 (d, J ) 8.9 Hz), 8.17 (m, 1H),
9.89 (m, 1H); 13C NMR (DMSO-d6) δ 20.92, 28.84, 47.28, 115.34,
126.15, 129.70, 160.56, 166.56; MS (ESI) m/z 192 (M - H)-, 194
(M + H)+.
Acknowledgment. The authors thank Carrow Wells for
postsynthesis compound processing and Matt Lochansky for
HRMS data collection. R.A.S. and D.P.M. acknowledge the
support of the NIH (Grant DK074652).
Supporting Information Available: General experimental
procedures, FRET and cell-based assay protocols, and compound
characterization data. This material is available free of charge via
References
(1) Giguere, V.; Yang, N.; Segui, P.; Evans, R. M. Identification of a
new class of steroid hormone receptors. Nature 1988, 331, 91–94.
(2) Giguere, V. To ERR in the estrogen pathway. Trends Endocrinol.
Metab. 2002, 13, 220–225.
(3) Mootha, V. K.; Handschin, C.; Arlow, D.; Xie, X.; St Pierre, J.; Sihag,
S.; Yang, W.; Altshuler, D.; Puigserver, P.; Patterson, N.; Willy, P. J.;
Schulman, I. G.; Heyman, R. A.; Lander, E. S.; Spiegelman, B. M.
Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phos-
phorylation gene expression that is altered in diabetic muscle. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 6570–6575.
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