Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2247
(5) Harris, H. A.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S.
Characterization of the Biological Roles of the Estrogen Recep-
tors, ER-alpha and ER-beta, in Estrogen Target Tissues In Vivo
Through the Use of an ER-alpha Selective Ligand. Endocrinology
2002, 143, 4172-4177.
(6) Krezel, W.; DuPont, S.; Krust, A.; Chambon, P.; Chapman, P.
F. Increased Anxiety and Synaptic Plasticity in Estrogen Recep-
tor â-Deficient Mice. Proc. Natl. Acad. Sc. U.S.A. 2001, 98,
12278-12282.
(7) Harris, H. A.; Albert, L. M.; Leathurby, Y.; Malamas, M. S.;
Mewshaw, R. E.; Miller, C. P.; Kharode, Y. P.; Marzolf, J.;
Komm, B. S.; Winneker, R. C.; Frail, D. E.; Henderson, R. A.;
Zhu, Y.; Keith, J. C. Evaluation of an Estrogen Receptor-â
Agonist in Animal Models of Human Disease. Endocrinology
2003, 144, 4241-4249.
(8) Nettles, K. W.; Sun, J.; Radek, J. T.; Sheng, S.; Rodriguez, A.
L.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S.; Greene,
G. L. Allosteric Control of Ligand Selectivity between Estrogen
Receptors R and â: Implications for Other Nuclear Receptors.
Mol. Cell 2004, 13, 317-327.
(9) Levenson, A. S.; Shafer, J. I. M.; Bentrem, D. J.; Pease, K. M.;
Jordan, V. C. Control of the Estrogen-Like Actions of the
Tamoxifen-Estrogen Receptor Complex by the Surface Amino
Acid at Position 351. J. St. Biochem. Mol. Biol. 2001, 76, 61-70.
(10) Willson, T. M.; Norris, J. D.; Wagner, B. L.; Asplin, I.; Baer, P.;
Brown, H. R.; Jones, S. A.; Henke, B.; Sauls, H.; Wolfe, S.;
Morris, D. C.; McDonnell, D. P. Dissection of the Molecular
Mechanism of Action of GW5638, a Novel Estrogen Receptor
Ligand, Provides Insight into the Role of the ER in Bone.
Endocrinology 1997, 138, 3901-3911.
(11) Shang, Y.; Brown, M. Molecular Determinants for the Tissue
Specificity of SERMS. Science 2002, 295, 2465-2468.
(12) Norris, J. D.; Paige, L. A.; Christensen, D. J. Peptide Antagonists
of the Human Estrogen Receptor. Science 1999, 285, 744-746.
(13) Iannone, M. A.; Consler, T. G.; Pearce, K. H.; Stimmel, J. B.;
Parks, D. J.; Gray, J. G. Mutliplexed Molecular Interactions of
Nuclear Receptors Using Fluorescent Microspheres. Cytometry
2001, 44, 326-337.
(14) Iannone, M. A.; Simmons, C. A.; Kadwell, S. H.; Svoboda, D. L.;
Vanderwall, D. E.; Deng, S. J.; Consler, T. G.; Shearin, J.; Gray,
J. G.; Pearce, K. H. Correlation Between In Vitro Peptide
Binding Profiles and Cellular Activities for Estrogen Receptor-
Modulating Compounds. Mol. Endocrinol. 2004, 18, 1064-1081.
(15) For a related benzopyranone-based SERM template, see Brady,
H.; Doubleday: M.; Gayo-Fung, L. M.; Hickman, M.; Khammu-
ngkhune, S.; Kois, A.; Lipps, S.; Pierce, S.; Richard, N.; Shevlin,
G.; Sutherland, M. K.; Anderson, D. W.; Bhagwat, S. S.; Stein,
B. Differential Response of Estrogen Receptors R and â to
SP500263, a Novel Potent Selective Estrogen Receptor Modula-
tor. Mol. Pharm. 2002, 3, 562-568.
(16) Stadlbauer, W.; Laschober, R.; Kappe, T. Potential Estrogens
and Antiestrogens. Part 3. Ylides of Heterocycles. Part 11. Pd-
Catalyzed Ring Closure Reactions to Benzofurans: a New and
Effective Approach to Azacoumestrols. Liebigs Ann. Chem. 1990,
6, 531-539.
adjusted to pH 2 with HCl (1.0 N), and extracted with EtOAc
(3 × 5 mL). The combined organic layer was washed with brine
(20 mL), dried over MgSO4, and evaporated. The crude solid
was purified over silica gel-60 via MPLC (EtOAc/hexane) to
afford 1a (0.043 g,16% yield over two steps; 96% purity) as a
yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.59-7.49 (m,
3H), 7.44 (s, H), 7.36-7.25 (m, 6H), 7.09-7.06 (m, 1H), 6.72-
6.69 (d, 2H), 6.36-6.31 (d, 1H), 2.71-2.63 (q, 2H), 1.17-1.12
(t, 3H). LC/MS tR 4.20 min (Conditions I) MS (M + H)+ 412.15.
3-(4-[(7-Hydroxy-2-ethyl-3-phenyl-4-quinolinyl)oxy-
phenyl])-2-propenoamide (1b). A CEM microwave tube was
charged with the phenol analogue of 5a (0.040 g, 0.095 mmol;
prepared by BBr3 treatment of 5a, using conditions disclosed
for 1a above), PPh3 (0.0137 g, 0.045 mmol), palladium(II)
acetate (0.005 g, 0.024 mmol), acrylamide (0.032 g, 0.46 mmol),
and Et3N (0.0387 mL, 0.29 mmol) in MeCN (2 mL). The
reaction was irradiated (150 W, 30 min, 175°C), filtered,
evaporated, poured into water (3 mL), and extracted with
EtOAc (3 × 5 mL). The combined organic layer was washed
with brine (5 mL), dried over MgSO4, and evaporated. The
crude solid was purified via HPLC (MeCN/H2O) to afford 1b
(0.021 g, 54% yield; 97% purity) as a yellow solid. 1H NMR
(300 MHz, CD3OD): δ 7.73 (d, 1H), 7.35 (m, 7H), 7.20 (m, 2H),
7.10 (dd, 2H), 6.63 (d, 2H), 6.46 (d, 1H), 2.78 (q, 2H), 1.15 (t,
3H). LC/MS tR 3.05 min (Conditions II); MS (M + H)+ 411.16.
N,N-Dimethyl 4-hydroxyphenyl-2-oxyethylamine (CAS
no. 100238-29-7). N,N-Dimethyl 4-hydroxyphenyl-oxyethy-
lamine18 (7.26 mmol) was prepared in two steps from N,N-
dimethyl-2-chloroethylamine HCl (14.6 mmol) and 4-methox-
yphenol (13.3 mmol; Cs2CO3, DMF, 80 °C, 4 h conditions)
followed by BBr3-mediated demethylation (DCM, 0 °C, 4 h):
1H NMR (300 MHz, DMSO-d6): δ 9.48, (bs, 1H), 6.81 (d, 2H),
6.68 (d, 2H), 4.17 (t, 2H), 3.44 (q, 2H), 2.83 (d, 6H). MS (M +
H)+ 182.00. C10H15NO2.
N,N-Dimethyl 4-[(2-Ethyl-7-hydroxy-3-phenyl-4-quino-
linyl)oxyphenyl]-2-oxyethylamine (8). Compound 8 (0.0148
g, 16% yield from 4-methoxyphenol; 99% purity) was prepared
as described previously by reaction of 7 (0.86 mmol) and N,N-
dimethyl-4-hydroxyphenyl-oxyethylamine (1.73 mmol; see con-
ditions for 5a) followed by BBr3-mediated demethylation
((DCM, -20 °C to room temperature, 4 h, see 1a): mp 184-
186°C. 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 1H), 7.48 (d,
1H), 7.37 (dd, 1H), 7.30 (m, 3H), 7.18 (m, 2H), 6.78 (m, 2H),
6.67 (m, 2H), 4.23 (t, 2H), 3.54 (t, 2H), 2.96 (s, 6H), 2.90 (q,
2H), 1.19 (t, 3H). LC/MS tR 1.40 min (Conditions I); MS (M +
H)+ 429.04. C27H28N2O3.
Acknowledgment. We thank David G. Jones, Roy
M. Katso, Matt Lochansky, Aaron B. Miller, Alan A.
Payne, and William J. Zuercher for support, and John
G. Gray and Brad R. Henke for helpful discussions.
(17) For related methodology applied to an imidazopyridine ER
template, see Patel, H. S.; Linn, J. A.; Drewry, D. H.; Hillesheim,
D. A.; Zuercher, W. J.; Hoekstra, W. J. New Synthetic Ap-
proaches to Estrogen Receptor Modulators: Imidazo[1,2-a]-
pyridines. Tetrahedron Lett. 2003, 44, 4077-4080.
(18) Blume, E.; Winkelmann, E.; Schaper, W.; Raether, W.; Dittmar,
W. Ger. Offen. Patent No. DE 3410070, 1985.
(19) The tamoxifen-selective peptide was discovered by Professor D.
P. McDonnell et al.: see McDonnell, D. P.; Chang, C.-Y.; Norris,
J. D. Development of Peptide Antagonists that Target ER-
Cofactor Interactions. J. Struct. Biochem. Mol. Biol. 2000, 74,
327-335.
(20) For a rat pharmacokinetic experimental description, see Brown,
K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Mook, R.;
Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.;
Harrington, W. W.; Novak, P. J.; Faison, W.; Binz, J. G.; Hashim,
M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.;
Tong, W. Q.; Menius, J. A.; Adkison, K.; Noble, S. A.; Willson,
T. M. A Novel N-Aryl Tyrosine Activator of PPARγ Reverses
the Diabetic Phenotype of the Zucker Diabetic Fatty Rat.
Diabetes 1999, 48, 1415-1424.
Supporting Information Available: Analyical data for
1c-h. This material is available free of charge via the Internet
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