ERβ ligands. Part 4: Synthesis and structure-activity relationships of a series of 2-phenylquinoline derivatives

Article abstract of DOI:10.1016/j.bmcl.2005.07.008

A new class of estrogen receptor β (ERβ) ligands based on the 2-phenylquinoline scaffold was prepared. Several analogues with C4 substitution displayed high affinity (3-5 nM) and significant selectivity (up to 83-fold) for ERβ. The best compound, 13b, was profiled as a selective partial agonist for ERβ at 1 μM in a cell-based transcriptional assay. Uterine weight bioassay of 13b indicated no activation of ERα in vivo.

Full text of DOI:10.1016/j.bmcl.2005.07.008

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4520–4525
ERb ligands. Part 4: Synthesis and structure–activity
relationships of a series of 2-phenylquinoline derivatives
An T. Vu,a,* Stephen T. Cohn,a Eric S. Manas,a Heather A. Harrisb and
Richard E. Mewshawa
aChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
bWomenꢀs Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
Received 3 June 2005; revised 30 June 2005; accepted 5 July 2005
Available online 10 August 2005
Abstract—A new class of estrogen receptor b (ERb) ligands based on the 2-phenylquinoline scaffold was prepared. Several ana-
logues with C4 substitution displayed high affinity (3–5 nM) and significant selectivity (up to 83-fold) for ERb. The best compound,
13b, was profiled as a selective partial agonist for ERb at 1 lM in a cell-based transcriptional assay. Uterine weight bioassay of 13b
indicated no activation of ERa in vivo.
Ó 2005 Elsevier Ltd. All rights reserved.
The estrogen receptor (ER) is a ligand-activated tran-
scription factor, which plays a crucial role in the devel-
opment, maintenance, and function of the mammalian
reproductive system, as well as other non-sexual tissues
such as the skeletal, cardiovascular, and central nervous
systems.1 The discovery in 1996 of a second subtype of
estrogen receptor, estrogen receptor b (ERb),2 with its
unique tissue distribution patterns and transcriptional
properties from those of ERa,3 has raised optimism
about ERb as a viable new drug target4 and offered
new opportunity for developing novel, tissue and cell-
selective estrogens.5 Recently, a report demonstrated a
potential therapeutic utility of ERb-selective agonists
in treating inflammation.6
tivity. Similar modest selectivity has been observed in a
number of other scaffolds.10 Diarylpropionitriles
(DPN)11 and biphenyls12 exhibited up to 70-fold selec-
tivity. Current medicinal chemistry efforts have yielded
several structural motifs with impressive ERb selectivity.
Indazoles13 and benzofurans14 showed selectivities up to
100-fold, whereas benzoxazoles15 displayed as high as
200-fold selectivity for ERb.
We recently reported a series of 6-phenylnaphthalenes
which was developed as a simplified structure to mimic
the genistein framework (Scheme 1).16 Docking studies
suggested that the 6-phenylnaphthalene scaffold could
Although the ligand binding domains (LBD) of ERa
and ERb share only modest homology (58% identity),
their ligand binding cavities are nearly identical, differ-
ing by only two amino acid residues (ERa Leu384 is re-
placed by ERb Met336, and ERa Met421 is replaced by
ERb Ile373).7 This slight variation in the binding cavities
presents a great challenge in developing ER subtype-
selective ligands. Phytoestrogens including the natural
product genistein (2),8 as well as constrained phytoestro-
gens9 displayed approximately 10- to 40-fold ERb selec-
OH
OH
OH
O
O
HO
HO
17β-Estradiol
Genistein
1
2
OH
4'
OH
4'
1
1'
4
5
8
5
1'
N
3
2
3'
7
6
3'
6
2
2'
2'
7
3
HO
HO
1
8
4
6-Phenylnaphthalene
2-Phenylquinoline
Keywords: Estrogen receptor ligands; 2-Phenylquinoline.
*
3
Corresponding author. Tel.: +1 484 865 8432; fax: +1 484 865
9399; e-mail: vua@wyeth.com
Scheme 1. Scaffold evolution.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.008

A. T. Vu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4520–4525
4521
exploit several binding orientations to achieve selectivi-
ty. The appropriate substituents placed at positions 1,
4, and 8 were shown to be essential to gain ERb selectiv-
ity by interacting favorably with ERb Ile373 and/or
repulsively with ERa Met421 using two different binding
orientations (Fig. 1).16 In particular, several derivatives
with C8 substitution displayed superior ERb selectivity
and affinity versus genistein. However, the synthetic
inaccessibility of certain functional groups at this posi-
tion prompted us to investigate the 2-phenylquinoline
scaffold (Scheme 1), which has a similar structural motif
as the 6-phenylnaphthalene. The facile assembly of this
heterocyclic ring core allows us to further explore the ef-
fects of substitution at positions 4 and 5 of the 2-phenyl-
quinoline scaffold, which correspond to positions 1 and
8 of the 6-phenylnaphthalene framework, respectively
(Fig. 1B).
synthesis (Scheme 3).19 Thus, alkoxycarbonylation of
4-methoxyacetophenones gave benzoylacetates 9, which
upon reaction with p-anisidine, followed by cyclization
furnished hydroxyquinolines 10a–c. Intermediates
10a,b were treated with POCl3, followed by demethyla-
tion to afford the 4-chloroquinolines 11a,b. Compounds
10a–c were also treated with POBr3 to give 12a–c, which
upon removal of the methyl protecting group afforded
the 4-bromo derivatives 13a–c. The chloro group of
11a was displaced by methoxide to furnish 4-methoxy-
quinoline 14. The cyano analogues 15a,b were prepared
by palladium-mediated coupling reaction of 12a,b with
Zn(CN)2,20 followed by demethylation.
The bromo derivatives 13a–c were also the common inter-
mediates from which a number of 4-substituted 2-phenyl-
quinolines could be prepared using various transition
metal-mediated cross-coupling reactions (Scheme 4).
Thus, Stille coupling of 13a,b with tributyl(vinyl)tin affor-
ded the vinyl analogues 16a,b, which upon reduction fur-
nished the ethyl targets 17a,b. Similarly, the alkynyl
derivatives 18a–c were prepared by reaction of 13a–c with
(trimethylsilylethynyl)tributyltin21 followed by desilyla-
tion. Suzuki reaction of 13b with phenylboronic acid
provided target 19. Coupling of 13a,b with (1-ethoxyvi-
nyl)tributyltin gave the acetyl analogues 20a,b after acid
hydrolysis. Subsequent reduction of the acetyl group of
20b yielded the hydroxyethyl derivative 21.
For the new 2-phenylquinoline template, we decided to
retain the hydroxyl groups at the 6 and 40 positions to
mimic the two terminal hydroxyl groups of genistein,
which is known to be essential for its binding to ER.8
Moreover, similar geometrical arrangement of the two
hydroxyl groups of the 6-phenylnaphthalene scaffold
has been shown to be optimal for both ERb affinity
and selectivity.16 In this report, we describe the synthesis
and structural–activity relationships (SARs) of a series
of 2-phenylquinolines. A number of these derivatives,
particularly those with C4 substitution, exhibited high
binding affinity and significant selectivity towards ERb.
The 2-phenylquinoline analogues were evaluated in a
competitive radioligand binding assay measuring the rel-
ative binding affinity (IC50) of the compounds for the
human ERa and ERb LBD.22 Results are presented in
Table 1. As expected, endogenous ligand 17b-estradiol
bound equally well to both ER isoforms in this assay.
All compounds in Table 1 were synthesized as shown in
Schemes 2–4. The synthesis began with the addition of
p-anisyllithium to 6-methoxyquinoline to give the 2-phe-
nylquinoline core 4 (Scheme 2).18 Subsequent demethyl-
ation using pyridine hydrochloride gave the parent
unsubstituted 2-phenylquinoline 5. Bromination of 4
with NBS gave 6, which upon initial deprotection using
pyridine hydrochloride at high temperature, the bromo
group was displaced by chloride exclusively to furnish
quinoline derivative 7. Thus, the brominated analogue
8 was obtained by an alternative demethylation method
using BBr3.
The unsubstituted quinoline 5 displayed some selectivity
(10-fold) for ERb, although binding affinity was modest.
The observed ERb selectivity of the 2-phenylquinoline
core (5) is consistent with the general observation that
the smaller overall binding pocket of ERb7 relative to
ERa would favor small and planar molecular struc-
tures,23 as well as the specific observation that aromatic
moieties appear capable of making a more favorable
interaction with ERb Met336 than ERa Leu384, given
the way these two side chains are presented to the bind-
The 2-phenylquinoline core can also be prepared using
a modification of the general Conrad–Limpach–Korr
A
Met336
Met336
B
His475
His475
Glu305
Glu305
Arg346
Arg346
Ile373
Ile373
Figure 1. Two possible binding orientations of 6-phenylnaphthalene 3 (white) when docked into the binding site of ERb–genistein complex.
Genistein (green) and key residues are shown colored by atom type. Arrows depict potential substitution sites for enhancement of ERb selectivity.
Reprinted with permission from Ref. 16. Copyright (2005) American Chemical Society.

4522
A. T. Vu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4520–4525
Table 1. Binding affinity for human ERa and ERb ligand binding domain
R2
OH
R1
N
HO
R3 R4
Compound
R1
R2
R3
R4
ERb IC50 (nM)a
ERa IC50 (nM)a
Selectivity (a/b)b
1
2
17b-Estradiol
Genistein
6-Phenylnaphthalene
3.6 1.6
3.2 1.0
395 181
211 74
1775 417
632 294
1140 71
213 38
246 93
212 87
283 113
783 273
504
1
41
13
10
21
13
46
46
50
83
22
8
10
16
4
7
3
5
H
H
H
H
F
H
H
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
171 60
30 11
7
H
H
H
H
H
H
F
H
8
H
Cl
88
2
11a
11b
13a
13b
13c
16a
16b
17a
17b
18a
18b
18c
15a
15b
20a
20b
19
4.6 2.1
5.3 3.2
4.3 2.3
3.4 1.5
Cl
Br
H
F
Br
Br
F
36
60
6
H
F
H
H
H
H
H
H
F
CH@CH2
CH@CH2
Et
44 11
52 13
79 55
75 15
27 12
750
385 104
634 287
1750 1018
1500 113
1309 451
4820
9
H
F
12
22
20
48
6
Et
H
F
C„CH
C„CH
C„CH
CN
F
H
F
H
H
H
H
H
H
H
28
7
455 107
1047 429
3138 285
3370 85
1815 615
6630
16
46
14
36
19
6
CN
23 10
221 13
93 28
211 118
1190
H
F
COMe
COMe
Ph
F
14
21
H
F
OMe
CH(OH)Me
>5000
>5000
ND
a IC50 values are the means of at least two experiments STD, determined from eight concentrations (performed in triplicate). Values without STDs
are for a single determination only.
b ERb selectivity is expressed as ERa IC50/ERb IC50 ratio.
ing pocket.24 Moreover, the weaker affinities of 5 for
both ER subtypes compared to those of the correspond-
ing unsubstituted 6-phenylnaphthalene 3 may be attrib-
uted to a greater desolvation penalty upon binding for
the quinoline moiety relative to naphthalene.25 Based
on the SAR and docking studies of the 6-phenylnaph-
thalene series,16 substitution at positions 4 and 5 of
the 2-phenylquinoline scaffold may provide the greatest
opportunity for further enhancing ERb selectivity by
interacting with the ERb Ile373/ERa Met421 residues.
As anticipated, derivative 7 with a chloro substituent
at the C5 position exhibited a 2-fold increase in ERb
selectivity, with a concomitant 5.7-fold improvement
in ERb binding affinity (7 vs 5). However, the larger bro-
mine group of 8 lowered both ERb affinity and selectiv-
ity (compared to 7), presumably due to steric repulsion
with the distal His475 residue.
OH
N
N
HO
Cl 7 (80%)
MeO
MeO
a
b
OMe
OMe
Next, we focused on the C4 substitution and examined a
variety of functional groups including electronegative,
electron-rich, aliphatic, aromatic, and polar substitu-
ents. Introduction of a halogen group led to approxi-
mately 40-fold increase in ERb affinity as shown by
11a and 13a (vs 5), both of which exhibited ERb IC50
values less than 5 nM. Moreover, since these analogues
had only a minor increase in ERa affinity, they dis-
played approximately 50-fold selectivity for ERb. This
affinity enhancement for both ER isoforms can be
attributed to a favorable overall hydrophobic effect
(due to the substituent itself as well as to reduced polar-
ity of the quinoline core induced by the electronegative
N
N
c
MeO
4 (10%)
6 (76%)
Br
b
d
OH
OH
N
N
HO
HO
5 (81%)
8 (71%)
Br
Scheme 2. Reagents and conditions: (a) 4-MeO-Ph-Li, Et2O, 0 °C; (b)
PyrÆHCl, 200 °C; (c) NBS, DMF, 40 °C; (d) BBr3, ClCH2CH2Cl,
40 °C.

A. T. Vu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4520–4525
4523
R2
O
O
O
R2
R2
OH
R1
a
b
OR
N
MeO
MeO
R1
R1
9, R = Me, Et
(94-97%)
HO
R2
c,d
R2
OH
R1
OMe
OH
R1
18a, R1, R2 = H (80%)
N
N
N
18b, R1 = F, R2 = H (86%)
18c, R1, R2 = F (87%)
R1
c, d
HO
MeO
HO
e
OH
Br
OH
Cl
N
13a, R1, R2 = H
10a, R1, R2 = H (69%)
11a, R1 = H (71%)
11b, R1 = F (62%)
F
13b, R1 = F, R2 = H
13c, R1, R2 = F
10b, R1 = F, R2 = H (49%)
10c, R1, R2 = F (53%)
HO
f
Ph
R2
e
a
f
19 (91%)
OH
R1
OH
R1
OMe
OH
N
N
N
N
R1
HO
HO
MeO
HO
Br
OMe
O
12a, R1, R2 = H (94%)
12b, R1 = F, R2 = H (95%)
12c, R1, R2 = F (66%)
14 (76%)
16a, R1 = H (69%)
16b, R1 = F (81%)
20a, R1 = H (78%)
20b, R1 = F (83%)
g, h
b
g
R2
d
OH
R1
OH
F
OH
OH
R1
N
N
N
N
R1
HO
HO
HO
HO
HO
Br
CN
17a, R1 = H (94%)
17b, R1 = F (97%)
13a, R1, R2 = H (82%)
13b, R1 = F, R2 = H (73%)
13c, R1, R2 = F (66%)
21 (98%)
15a, R1 = H (78%)
15b, R1 = F (87%)
Scheme 4. Reagents and conditions: (a) Bu3SnCH@CH2, Pd(PPh3)4,
tol., reflux; (b) H2, Pd/C, EtOAc; (c) Bu3SnC„C-TMS, Pd(PPh3)4,
tol., reflux; (d) K2CO3, MeOH; (e) Ph-B(OH)2, Pd(PPh3)4, DME, aq
Na2CO3, reflux; (f) Bu3Sn(OEt)C@CH2, Pd(PPh3)4, tol., reflux, then
1 N HCl; (g) NaBH4, EtOH.
Scheme 3. Reagents and conditions: (a) NaH, CO(OMe)2 or
CO(OEt)2, 1,4-dioxane, reflux; (b) p-anisidine, cat. p-TsOH, toluene,
80 °C, then Ph2O, 250 °C; (c) POCl3, reflux; (d) BBr3, ClCH2CH2Cl,
40 °C; (e) POBr3, DMF, 70 °C; (f) NaOMe, MeOH, 150 °C; (g)
Zn(CN)2, Pd(PPh3)4, DMF, 80 °C; (h) PyrÆHBr, 200 °C.
respectively). Similar selectivity enhancement induced
by the 30-fluoro substituent has been observed with
other scaffolds as well.14–16 A structure-based explana-
tion for this effect has been proposed elsewhere.17 Sur-
prisingly, the addition of a second fluoro group at the
50 position (13c and 18c vs 13a,b and 18a,b, respectively)
proved to be detrimental. A possible reason for this loss
of activity is most likely due to the electrostatic repul-
sion between one of the fluoro substituents and the side
halogen26), and to additional van der Waals interactions
between the halogen and surrounding residues. Further-
more, the significantly smaller increase in ERa affinity is
presumably due to a less favorable interaction between
the halogen atom and the ERa Met421 side chain.
Although the relative contribution of dispersion, elec-
trostatics, and exchange repulsion is unclear, it is possi-
ble that the electronegativity of the halogens and the
methionine sulfur makes an unfavorable electrostatic
contribution to the total interaction.17 Small aliphatic
groups such as ethyl (17a), vinyl (16a), alkynyl (18a),
and small electron-withdrawing cyano (15a) group all
showed some ERb affinity enhancement (relative to 5),
but with minimal or no effect on selectivity, whereas
the larger acetyl (20a) and phenyl (19) groups provided
only slight selectivity improvement. Interestingly, the
methoxy group (14) caused a great loss of activity, pre-
sumably due to the unfavorable basicity of the quinoline
core induced by the electron-rich methoxy group. Intro-
duction of the polar hydroxyethyl group (21) resulted in
a complete loss of affinity.
chain of Glu305.
15 We point out that 13b is the most po-
tent and selective of the 2-phenylquinolines reported,
with an ERb IC50 value of 3.4 nM and 83-fold selectiv-
ity. Docking of 13b to the binding pocket of the ERb
LBD/WAY-202196 cocrystal structure (PDB accession
code 1YYE16) places the bromo group in close proxim-
ity to the ERb Ile373 ! ERa Met421 residue substitution
(analogous to the cyano group of WAY-202196, see
Fig. 2 and Ref. 16), suggesting that a differential interac-
tion with these residues may contribute to the enhanced
ERb selectivity. Modulation of the quinoline electronic
structure (and thus interaction with ERb Met336 ! ERa
Leu384
)
may also contribute to the selectivity
enhancement.16
With respect to phenyl ring substitution, introduction of
a 30-fluoro group generally led to a subtle increase in
ERb selectivity as shown by derivatives 13b, 15b, 17–
18b, and 20b (relative to 13a, 15a, 17–18a, and 20a,
Compound 13b was further evaluated in a cell-based
transcriptional assay measuring its ability to regulate
human keratin19 (KRT19) mRNA. This gene is upreg-

4524
A. T. Vu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4520–4525
References and notes
Met336
(ERα Leu384
)
1. Selective Estrogen Receptor Modulators; Manni, A.,
Verderame, M. F., Eds.; Humana Press: Totowa, NJ,
2002.
His475
Glu305
2. (a) Mosselman, S.; Polman, J.; Dijkema, R. FEBS Lett.
1996, 392, 49; (b) Kuiper, G. G.; Enmark, E.; Pelto-
Huikko, M.; Nilsson, S.; Gustafsson, J.-A. Proc. Natl.
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Wallace, O. B.; Richardson, T. I.; Dodge, J. A. Curr. Top.
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Arg346
Ile373
(ERα Met421
)
Figure 2. Compound 13b docked to ERb LBD/WAY-202196 complex.
Docking calculations were performed as described in Ref. 12.
6. 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.;
Hederson, R. A.; Zhu, Y.; Keith, J. C., Jr. Endocrinology
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Bonn, T.; Thorsell, A.-G.; Engstrom, O.; Ljunggren, J.;
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ulated by 17b-estradiol in human prostate cancer cells
(LNCaPLN3) engineered to express either ERa or
ERb and thus can be used to determine agonist/antago-
nist activity of compounds.10b Analogue 13b was tested
at 1 lM and was compared to that of 10 nM 17b-estra-
diol. It was found to be inactive via ERa and was about
60% as efficacious as 17b-estradiol via ERb. When test-
ed in combination with 17b-estradiol, there was no
marked antagonist activity. The results thus suggest that
13b is a selective partial agonist for ERb at 1 lM.
8. Kuiper, G. G.; Lemmen, J. G.; Carlsson, B.; Corton, J. C.;
Safe, H.; Saag, P. T.; Burg, B.; Gustafsson, J. Endocrinol-
ogy 1998, 139, 4252.
9. Miller, C. P.; Collini, M. D.; Harris, H. A. Bioorg. Med.
Chem. Lett. 2003, 13, 2399.
Compound 13b was also evaluated in a highly sensitive
uterine weight estrogenic bioassay measuring the weight
gain in sexually immature mouse uterus. Because rodent
uterus expresses primarily ERa, this model can be used
to assess the in vivo ER selectivity of compounds. Sexu-
ally immature mice were dosed subcutaneously for 4
days with 50 mg/kg of 13b in an oil-based vehicle.17 In
contrast to 17b-estradiol, which increased organ weight
4-fold, no significant uterine weight gain was observed
for 13b, indicating no ERa activation in this in vivo
model.
10. (a) Schopfer, U.; Schoeffter, P.; Bischoff, S. F.; Nozulak,
J.; Feuerbach, D.; Floersheim, P. J. Med. Chem. 2002, 45,
1399; (b) Yang, C.; Edsall, R., Jr.; Harris, H. A.; Zhang,
X.; Manas, E. S.; Mewshaw, R. E. Bioorg. Med. Chem.
2004, 12, 2553; (c) Yang, W.; Wang, Y.; Ma, Z.; Golla, R.;
Stouch, T.; Seethala, R.; Johnson, S.; Gungor, T.; Feyen,
J. H. M.; Dickson, J. K., Jr. Bioorg. Med. Chem. Lett.
2004, 14, 2327.
11. Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 4230.
12. Edsall, R. J.; Harris, H. A.; Manas, E. S.; Mewshaw, R. E.
Bioorg. Med. Chem. 2003, 11, 3457.
13. Angelis, M. D.; Stossi, F.; Carlson, K. A.; Katzenellenb-
ogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2005,
48, 1132.
14. Collini, M. D.; Kaufman, D. H.; Manas, E. S.; Harris, H.
A.; Henderson, R. A.; Xu, Z. B.; Unwalla, R. J.; Miller, C.
P. Bioorg. Med. Chem. Lett. 2004, 14, 4925.
15. Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Guna-
wan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.;
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16. Mewshaw, R. E.; Edsall, R., Jr.; Yang, C.; Manas, E. S.;
Zhang, B. X.; Henderson, R. A.; Keith, J. C., Jr.; Harris,
H. A. J. Med. Chem. 2005, 48, 3953.
17. Manas, E. S.; Unwalla, R. J.; Xu, Z. B.; Malamas, M. S.;
Miller, C. P.; Harris, H. A.; Hsiao, C.; Akopian, T.; Hum,
W.-T.; Malakian, K.; Wolfrom, S.; Bapat, A.; Bhat, R. A.;
Stahl, M. L.; Somers, W. S.; Alvarez, J. C. J. Am. Chem.
Soc. 2004, 126, 15106.
In summary, we have identified the 2-phenylquinolines
as a new series of ERb-selective ligands. Substitution
at the C4 position, particularly with electronegative
groups, was essential for ERb selectivity. Further selec-
tivity enhancement could be achieved by incorporating a
fluoro group at the 30 position of the phenyl ring. A
number of substituted 2-phenylquinolines displayed
superior ERb affinity and selectivity to that of genistein.
Quinoline 13b, which was the best compound of this
study, was found to be a selective partial agonist for
ERb in a cell-based transcriptional assay. Its uterine
weight bioassay showed no significant uterine stimula-
tion, suggesting that this compound will not activate
ERa in vivo. Efforts are continuing in our laboratories
to expand upon our multiple binding orientation strate-
gy to maximize ERb selectivity.
18. Hamana, M.; Takeo, S.; Noda, H. Chem. Pharm. Bull.
1977, 25, 1256.
Acknowledgment
19. Kohno, Y.; Awano, K.; Miyashita, M.; Ishizaki, T.;
Kuriyama, K.; Sakoe, Y.; Kudoh, S.; Saito, K.; Kojima,
E. Bioorg. Med. Chem. Lett. 1997, 7, 1519.
We thank the Wyeth Discovery Analytical Chemistry
Department for the spectral data.

A. T. Vu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4520–4525
4525
20. Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.;
Pipik, B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994,
24, 887.
25. LogP measurements (octanol–water) for naphthalene
generally exceed that of quinoline by at least one
log unit, indicating greater likelihood of partitioning
21. Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549.
22. Harris, H. A.; Bapat, A. R.; Gonder, D. S.; Frail, D. E.
Steroids 2002, 67, 379.
into a hydrophobic environment. See for example:
Rogers, K.; Cammarata, A. J. Med. Chem. 1969, 12,
692.
23. Compound 5 was previously reported to exhibit some
degree of ERb selectivity: Wallace, O. B.; Lauwers, K. S.;
Jones, S. A.; Dodge, J. A. Bioorg. Med. Chem. Lett. 2003,
13, 1907.
24. Manas, E. S.; Xu, Z. B.; Unwalla, R. J.; Somers, W. S.
Structure 2004, 12, 2197.
26. B3LYP/6-31G** calculations utilizing a Poisson–Boltz-
mann self-consistent reaction field model (Jaguar 6.0;
Schro¨dinger, LLC, Portland, OR) indicate that
a
4-chloro substituent decreases both the quinoline dipole
moment and the aqueous desolvation energy.