Estrogen Receptor Ligands. II. Discovery of Benzoxathiins as Potent, Selective Estrogen Receptor α Modulators

Article abstract of DOI:10.1021/jm034243o

The discovery and synthesis of dihydrobenzoxathiins as potent, ERα subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay i

Full text of DOI:10.1021/jm034243o

© Copyright 2004 by the American Chemical Society
Volume 47, Number 9
April 22, 2004
Letters
Estr ogen Recep tor Liga n d s. II. Discover y
of Ben zoxa th iin s a s P oten t, Selective
Estr ogen Recep tor r Mod u la tor s
Seongkon Kim,*,‡ J ane Y. Wu,‡ Elizabeth T. Birzin,‡
Katalin Frisch,‡ Wanda Chan,‡ Lee-Yuh Pai,‡
Yi Tien Yang,‡ Ralph T. Mosley,‡
F igu r e 1.
Paula M. D. Fitzgerald,‡ Nandini Sharma,‡
J ohanna Dahllund,† Ann-Gerd Thorsell,†
Frank DiNinno,‡ Susan P. Rohrer,‡
The recent discovery of a second estrogen receptor
subtype (ERâ)6 provided an additional approach for the
identification of “ideal SERMs” with improved side effect
profiles. Whereas tamoxifen and raloxifene are tissue
selective SERMs, they bind with comparable affinity to
both receptor subtypes and thereby raise the possibility
that there may be advantages to receptor subtype
selective compounds.
J ames M. Schaeffer,‡ and Milton L. Hammond‡
Departments of Medicinal Chemistry, Atherosclerosis and
Endocrinology, Merck Research Laboratories, P.O. Box 2000,
800-B109 Rahway, New J ersey 07065, and Karo Bio AB,
Novum, S-14157 Huddinge, Sweden
In a previous communication,7 we identified ERR
subtype selective SERMs or SERAMs that centered on
the isoflavanone core structure. Although these com-
pounds, exemplified by compound 1, type I (where R1
) H, R2 ) R3 ) OH, X ) CO; Figure 1), exhibited a
greater affinity for ERR over ERâ (∼70-fold selectivity),
only modest binding and in vivo potency were observed.
Our search for more potent subtype selective SERMs
or SERSMs1c prompted an expanded structure-activity
relationship (SAR) evaluation of the series. We report
the results of this investigation leading to the discovery
of the benzoxathiin core, type I (X ) S).
A representative synthesis of the key compounds is
described in Scheme 1. The thioketone 9 underwent re-
ductive cyclization with Et3SiH/TFA in dichlorometh-
ane at 0 °C to yield only the cis-dihydrobenzoxathiin
10, as we have previously described.8 The Mitsunobu
alkylation of the phenol 10 with 1-(2-hydroxyethyl)-
piperidine was utilized for the installation of the basic
side chain. Sequential deprotection of the benzyl group,
under transfer hydrogenation conditions, followed by
desilylation with TBAF in the presence of HOAc, yielded
the desired compound 4. The trans isomer 14 and benzo-
xathiin 16 were prepared according to literature pro-
cedures with minor modifications.9 Thus, reduction of
9 with LiEt3BH, followed by acid (Amberlyst-15) cata-
lyzed cyclization in toluene at room temperature, af-
Received November 24, 2003
Abstr a ct: The discovery and synthesis of dihydrobenzoxathi-
ins as potent, ERR subtype selective ligands are described. The
most active analogue, 4-D, was found to be 50-fold selective
in a competitive binding assay and 100-fold selective in a
transactivation assay in HEK-293 cells. The R selectivity was
postulated to lie in the interaction of the sulfur atom of the
benzoxathiin ring with the two discriminating residues in the
binding pocket of the receptor isoforms.
The selective estrogen receptor modulators (SERMs)1
have been developed owing to the potential ability to
antagonize the detrimental effects of estrogen on uterine
and breast tissue while producing estrogen-like effects
on bone and the cardiovascular system.2 The utility of
SERMs is exemplified by the use of tamoxifen3 for the
prevention and treatment of breast cancer and ralox-
ifene4 for the treatment and prevention of osteoporosis.
Over recent years, several additional SERMs5 have
entered late stages of clinical trials for a variety of
indications. Although the current SERMs have clear
advantages over conventional HRT, they retain some
of the disadvantages as well.
* To whom correspondence should be addressed. Phone: 732-594-
8439. Fax: 732-594-9556. E-mail: Seongkon_kim@merck.com.
‡ Merck Research Laboratories.
† Karo Bio AB.
10.1021/jm034243o CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/20/2004

2172 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9
Letters
Sch em e 1a
a
Reagents: (i) Et3SiH, TFA, 0 °C, 90%; (ii) PPh3, DIAD, 1-(2-hydroxyethyl)piperidine, THF, 40 °C, 65-75%; (iii) (a) Pd, HCO2NH4, (b)
TBAF, HOAc, THF, room temp, 43-55% for two steps (a and b); (iv) LiEt3BH, THF, 0 °C; (v) Amberlyst-15, toluene, room temp, 93% for
two steps (iv and v); (vi) TsOH, toluene, reflux, 40%.
Sch em e 2a
a
Reagents: (i) (a) excess mCPBA, CH2Cl2, room temp, (b) saturated NaHSO3, saturated NaHCO3, room temp, 1 h, 75% (steps a and
b); (ii) (a) Pd, HCO2NH4, (b) TBAF, HOAc, THF, room temp, 64% for two steps (a and b); (iii) (a) TBSCl, EtN(i-Pr)2, DMF, 89%, (b) 2 equiv
of mCPBA, CH2Cl2, -10 °C, 2 h, 78%; (iv) (a) saturated NaHSO3, saturated NaHCO3, room temp, 1 h, 65%, (b) TBAF, HOAc, THF, room
temp, 80%.
forded 13 in 93% yield. Conversion of thioketone 9 into
thiin 15 was achieved by dehydrative cyclization with
TsOH in refluxing toluene. Both 13 and 15 were con-
verted to 14 and 16, respectively, as described above.
As shown in Scheme 2, exhaustive oxidation of 11 with
excess mCPBA at room temperature provided the sul-
fone N-oxide (not shown), which was then selectively
reduced back to the corresponding free amine 17 in 75%
yield. The deprotection tactics described above afforded
sulfone 8. Similarly, sulfoxide 7 was synthesized from
4-D.
Chiral resolution of the dihydrobenzoxathiin 10 was
realized by HPLC, using a Chiracel AD column and 30%
IPA/hexane as the eluant, to provide the dextrorotatory
enantiomer 10-D and the levorotatory enantiomer 10-
L. Both chiral precursors were converted to 4-D and 4-L,
respectively,10 utilizing the same procedures as de-
scribed in Scheme 1.
The ligand binding domain of ERR (residues 307-554)
in complex with 4-D was crystallized in space group P65-
22, with cell dimensions a ) b ) 58.48 Å, c ) 276.08 Å.
Data to 1.9 Å resolution were measured at beamline 17-
ID of the Advance Photon Source. The data were
processed with program X-GEN, which yielded an Rmerge
of 0.070 for the data from 10.0 to 1.9 Å and 0.356 for
the data from 2.02 to 1.90 Å. The structure was refined
using program SHELXL, with final values for Rwork and
Rfree of 0.218 and 0.272 for the data from 10.0 to 1.90 Å
resolution. 99.1% of the residues in the refined model
were in the most favorable and additionally allowed
regions of a Ramachandran plot. The rms errors for
bond distances and angles were 0.005 and 0.020,
respectively. Coordinates and structure factors have
been deposited with the Protein Data Bank (entry 1SJ 0.
Our compounds were primarily tested for intrinsic
activity in an ER binding assay.11 Potency and selectiv-
ity of selected compounds were further assessed in a
cellular transactivation assay utilizing HEK 293 cells
stably cotransfected with either human ERR or ERâ and
the alkaline phosphatase reporter gene. The inhibition
of the proliferative activity of estradiol along with the
estrogenic activity was measured in vivo using an
immature rat uterine weight gain assay.12
The binding affinities of 1-8 to the human ERR and
ERâ receptors are summarized in Table 1. Given the
previous hypothesis7 that the crucial difference respon-
sible for the R selectivity of lead 1 lies in the interaction
of its carbonyl with the two discriminating residues in
the binding pocket of the two receptor isoforms (Leu 384
for ERR, Met 354 for ERâ),13 our initial efforts were
focused on the examination of point changes directed
at the carbonyl region of the isoflavanone. Replacement

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9 2173
11
Ta ble 1. Estrogen Receptor Binding Affinities, IC50
IC50 (nM)11
ERâ
compda
X
R1
R2
R3
ERR
1
2
3
4
CO
CH2
S
S
S
S
SO
SO2
H
H
H
OH
OH
H
OH
OH
OH
OH
OH
H
H
H
OH
OH
OH
OH
H
OH
OH
OH
39
2732 (n ) 3)
6.7
1.6
3.0
6.2
10
8.9
45
143 (n ) 5)
183
5
6
70
7b
H
H
>104
1090
1.3
1.8
>104
5950
1.1
8
E-2
ralox
12 (n ) 7)
a
b
All compounds are racemates. Chiral.
F igu r e 2. Molecular modeling of 4-D (white) against ralox-
ifene (purple). HERR is depicted in purple and hERâ in green.
Residue numbering is hERR unless otherwise indicated.
of the carbonyl moiety with CH2 (2)7 significantly
improved the ERâ binding affinity (8.9 nM) but had
little effect on the ERR binding, thereby reducing its
selectivity to about 1-fold. This result supported our
hypothesis that a smaller group might enhance binding
to the ERâ receptor by eliminating the proposed unfa-
vorable steric and electronic interactions that the Met
354 residue presents. Conversely, R selectivity was
regained by incorporation of the larger, more polar
sulfur atom (3), which also resulted in increased recep-
tor affinity compared to 1. Within the limits of the
binding assay, switching the hydroxyl from position 7
to 6 (4) was without consequence; however, this change
had a profound effect on the pharmacokinetics.14 To
confirm the structural basis for the selectivity profile
of 4, molecular modeling of multiple conformers of each
of the two cis enantiomers was evaluated in the context
of hERR and hERâ ligand binding domains. The docking
and energy minimization approach, which will be de-
scribed elsewhere, identified a binding mode of 4 with
the absolute configuration of [2S,3R] as being the most
likely to explain the SAR and would assign that absolute
stereochemistry to 4-D. This binding mode posits the
dihydrobenzoxathiin ring system of 4-D in the ben-
zothiophene location of raloxifene as it is bound to hERR
determined crystallographically (PDB entry 1ERR),
which is depicted in Figure 2. From the modeled results,
the conjecture that the out-of-plane pucker of the sp3-
hybridized sulfur in the dihydrobenzoxathiin ring is
responsible for the same interactions described above
is consistent with the prior observation. This pucker
clearly directs the sulfur toward one of the two selectiv-
ity regions that line the binding cavity, whereas the sp2-
hybridized sulfur of raloxifene is directed away from this
selectivity region. The proposed binding mode and
absolute stereochemistry were later confirmed crystal-
lographically as shown in Figure 3.
In contrast to the isoflavanone series7 where both
hydroxyls at R2 and R3 were required for optimal
binding and selectivity, only modest decreases were
observed upon removal of the hydroxyl at R3 (5). The
relative importance of the benzoxathiin ring hydroxyl,
R1, is measured by the more dramatic impact on these
parameters observed with 6.16 A similar trend was also
reported for raloxifene derivatives.17 The incorporation
of a polar group, like sulfoxide 7, had a detrimental
effect on the binding affinity, implying that a negative
charge on oxygen is not tolerated at all in this hydro-
phobic region of the receptor.18 A similar effect was also
observed with the sulfone moiety (8). From these data,
it is clear that activity and selectivity correlate well with
the nature of the X moiety.
To enhance the SAR of the benzoxathiin core, the
stereochemistry at C2,3 was investigated, and these
results are described in Table 2. As observed with
isoflavanones,7 the cis stereochemistry at C2,3 proved
to be an absolute requirement for the maintenance of
an optimal antagonist/agonist activity profile in vivo,
Ta ble 2. Binding Affinities and in Vivo Data
binding affinity, IC50 (nM)11
HEK 293 cells, IC50 (nM)
uterine weight assay (sc),12
compd
C2,3
human ERR
human ERâ
ERR
ERâ
% inhibition @ 1mpk/% control @1 mpk
4
(()-cis
3.0
0.8
23
17
1.6
143 (n ) 5)
45 (n ) 36)
287
276
5.1
9.6
0.8
353
188
5.1
52
97
3876
1404
159
77/5.0
92/0.4a
16/1.0
18/20
55/45
4-Db
4-L
14
cis-[2S,3R]
cis-[2R,3S]
(()-trans
olefin
16
a
b
At a po dose of 0.3 mpk (1.0 mpk), 80% (99%) inhibition and 11.4% (9.0%) agonism was observed. The absolute configuration was
confirmed by X-ray crystallography of 4-D complexed with ERR-LBD307-554.

2174 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9
Letters
Department at MRL, West Point, PA, for conducting the
bone mineral density evaluations, to Dr. Bernard K.
Choi for supplying HRMS, and to Dr. Lawrence Colwell
and Ms. Susan Li for pharmacokinetic determinations.
Use of the Advance Photon Source beamline 17-ID was
supported by the companies of the Industrial Macro-
molecular Crystallography Association through a con-
tract with Illinois Institute of Technology.
Su p p or tin g In for m a tion Ava ila ble: Characterization
(1H NMR, LC/MS, and HRMS) of 4-D, 5, 7, 8, 14, and 16. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Refer en ces
(1) Recent reviews on SERMs: (a) J ordan, V. C. Antiestrogens and
Selective Estrogen Receptor Modulators as Multifunctional
Medicines. 1. Receptor Interactions. J . Med. Chem. 2003, 46,
883-908. (b) J ordan, V. C. Antiestrogens and Selective Estrogen
Receptor Modulators as Multifunctional Medicines. 2. Clinical
Considerations and New Agents. J . Med. Chem. 2003, 46, 1081-
1111. (c) Meegan, M. J .; Lloyd, D. G. Advances in the Science of
Estrogen Receptor Modulation. Curr. Med. Chem. 2003, 10, 181-
210.
(2) Park, W. C.; J ordan, V. C. Selective estrogen receptor modula-
tiors (SERMS) and their roles in breast cancer prevention.
Trends Mol. Med. 2002, 8, 82-88.
(3) J ordan, V. C. A current view of tamoxifen for the treatment and
prevention of breast cancer. Br. J . Pharmacol. 1993, 110, 507-
517.
F igu r e 3. Comparison of crystallographic (cyan) to molecular
modeling results for 4-D (white). HERR is depicted in purple
and hERâ in green.
as evidenced by a comparison of the uterine weight data
for 4 and the trans 14 (77% inhibition and 5.0% agonism
versus 18% inhibition and 20% agonism). The poor
activity exhibited by 14 paralleled the weak estradiol
antagonism observed in the functional assay (HEK ERR
) 188 nM). Interestingly, the planar thiin 16, with
receptor affinity and functional activity comparable to
those of 4, produced a significant increase in uterine
weight (45% agonism) along with a modest antiprolif-
erative effect (55% inhibition). These results suggested
that the coplanar orientation of the side chain present
in 16 may contribute to uterine stimulation, as seen
with tamoxifen and raloxifene derivatives where the
carbonyl hinge has been excised to similarly generate
a coplanar orientation of the side chain.19
As suggested by molecular modeling, only the single
enantiomer 4-D reproduced the activities exhibited by
the racemate 4.20 Thus, when dosed sc, 4-D potently
inhibited the estradiol-driven uterine growth in im-
mature rats (92% inhibition), while only weak utero-
tropism (0.4%) was observed. Even at a lower oral dose
of 0.3 mpk, 4-D suppressed nearly 80% of the estrogen
stimulus on the uterus and the agonist activity did not
appear to be dose-dependent (ca. 10% agonism at both
0.3 and 1.0 mpk).14
In addition, 4-D, in the appropriate rat models, was
shown to effectively inhibit ovariectomy-induced bone
resorption, lower serum cholesterol levels, and estradiol-
driven endometrial explant growth. Such a profile of
activities clearly establish this new class of compounds
as potent SERAMs that warrant further investigation
and will be the subject of future communications from
these laboratories.
In summary, we have disclosed herein a novel ERR
selective SERM (4-D) or SERAM that displays low-nano-
molar binding affinity and subnanomolar functional
activity. This compound exhibited excellent in vivo effi-
cacy for the suppression of estradiol-driven uterine proli-
feration, with minimal uterotropic activity. The molec-
ular modeling of 4-D suggested that the sulfur moiety
may be crucial to maintaining subtype selectivity.
(4) Sato, M.; Grese, T. A.; Dodge, J . A.; Bryant, H. U.; Turner, C.
H. Emerging Therapies for the Prevention or Treatment of
Postmenopausal Osteoporosis. J . Med. Chem. 1999, 42, 1-24.
(5) EM-652: Labrie, M.; Labrie, C.; Belanger, A.; Simard, J .;
Giguere, V.; Tremblay, A.; Tremblay, G. EM-652 (SCH57068),
a pure SERM having complete antiestrogenic activity in the
mammary gland and endometrium. J . Steroid Biochem. Mol.
Biol. 2001, 79, 213-225. Lasofoxifene: Ke, H. Z.; Paralkar, V.
M.; Grasser, W. A.; Crawford, D. T.; Qi, H.; Simmons, H. A.;
Pirie, C. M.; Chidsey-Frink, K. L.; Owen, T. A.; Smock, S. L.;
Chen, H. K.; J ee, W. S. S.; Cameron, K. O.; Rosati, R. L.; Brown,
T. A.; DaSilva J ardine, P.; Thompson, D. D. Effects of CP-336,-
156, a New Nonsteroidal Estrogen Agonist/Antagonist, on Bone,
Serum Cholesterol, Uterus, and Body Composition in Rat
Models. Endocrinology 1998, 139, 2068-2076. Bazedoxifene:
Miller, C. P.; Collini, M. D.; Tran, B. D.; Harris, H. A.; Kharode,
Y. P.; Marzolf, J . T.; Moran, R. A.; Henderson, R. A.; Bender, R.
H. W.; Unwalla, R. J .; Greenberger, L. M.; Yardley, J . P.; Abou-
Gharbia, M. A. A.; Lyttle, C. R.; Komm, B. S. Design, Synthesis,
and Preclinical Characterization of Novel, Highly Selective
Indole Estrogens. J . Med. Chem. 2001, 44, 1654-1657.
(6) (a) Kuiper, G. G. J . M.; Enmark, E.; Pelto-Huikko, M.; Nilsson,
S.; Gustafsson, J . A. Cloning of a novel estrogen receptor
expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 5925-5930. (b) Mosselman, S.; Polman, J .; Dijkema,
R. Identification and Characterization of
a Novel Human
Estrogen Receptor. FEBS Lett. 1996, 392, 49-53.
(7) Chen, H. Y.; Dykstra, K. D.; Birzin, E. T.; Frisch, K.; Chan, Y.;
Yang, Y.; Mosley, R. T.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J .
M.; Hammond, M. L. Estrogen Receptor Ligands: I. The
Discovery of Flavanoids with Subtype Selectivity. Bioorg. Med.
Chem. Lett., in press.
(8) Kim, S.; Wu, J . W.; Chen, H. Y.; DiNinno, F. Dehydrative
Reduction: A Highly Diastereoselective Synthesis of Syn-bisaryl-
(or Heteroaryl) Benzodioxane and Dihydrobenzoxathiins. Org.
Lett. 2003, 5, 685-688.
(9) (a) Arnoldi, A.; Bassoli, A.; Caputo, R.; Merlini, L.; Palumbo, G.;
Pedatella, S. Synthesis of 3-Aryl-1,4-benzoxathianes: Applica-
tion to the Preparation of a Sweet Compound. J . Chem. Soc.,
Perkin Trans. 1 1994, 1241-1244. (b) Parham, W. E.; Willette,
C. L. Heterocylclic Vinyl Ethers. XVII. Benzo-1,4-oxathiadiene-
2-aldehyde, 2-Methylbenzo-1,4-oxathiadiene, and 3-Methylbenzo-
1,4-oxathiadiene. J . Org. Chem. 1960, 25, 53-56.
(10) 4-D: [R]D +276.8° (c 0.49, MeOH). 4-L: [R]D -263.3° (c 0.515,
MeOH). 10-D: [R]D +184.4° (c 0.725, MeOH). 10-L: [R]D -188.5°
(c 0.740, MeOH).
(11) The IC50 values were generated in an estrogen receptor ligand
binding assay. This scintillation proximity assay was conducted
in NEN Basic Flash plates using tritiated estradiol and full-
length recombinant human ERR and ERâ proteins with incuba-
tion times of 3-23 h. In our experience, this assay provides IC50
values that are reproducible to within a factor of 2-3. Most
Ack n ow led gm en t. The authors are grateful to Dr.
Donald Kimmel and his associates in the Bone Biology

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9 2175
compounds are single-point determinations. The binding results
for 4-D reflect an average of 36 determinants at of
incubation. For estradiol, the binding data reflect an average of
over 100 determinants at 3 h of incubation.
N.; Tjoa, C. M.; Sweetnam, P. M.; Cole, M. J .; Arriola, M. W.;
Gauthier, J . W.; Crawford, D. T.; Nickerson, D. F.; Pirie, C. M.;
Qi, H.; Simmons, H. A.; Tkalcevic, G. T. Discovery and Preclini-
cal Pharmacology of a Novel, Potent, Nonsteroidal Estrogen
3
h
(12) Twenty-day-old intact female Sprague-Dawley rats were treated
(sc) with test compounds for 3 days at 1 mpk. The uteri wet
weights were determined on day 4, and dry weights were
determined after air-drying the tissue samples for 3 days. The
antiestrogenic activity of the compounds was determined by
coadministration of the compound with a subcutaneous injection
of 17-â-estradiol and reported as % inhibition. The estrogenic
activity (partial agonism) of the compounds was determined by
administering the test compound without estradiol and reported
as % control.
Receptor Agonist/Antagonist, CP-336156,
a Diaryltetrahy-
dronaphthalene. J . Med. Chem. 1998, 41, 2928-2931.
(16) As in raloxifene, the hydroxyl at R1 is presumably responsible
for docking the ligand into the water channel of the receptor.
(17) Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; et al.
Structure-Activity Relationships of Selective Estrogen Receptor
Modulators: Modifications to the 2-Arylbenzothiophene Core of
Raloxifene. J . Med. Chem. 1997, 40, 146-167.
(18) Wallace, O. B.; Lauwers, K. S.; J ones, S. A.; Dodge, J . A.
Tetrahydroquinoline-Based Selective Estrogen Receptor Modu-
lators (SERMs). Bioorg. Med. Chem. Lett. 2003, 13, 1907-1910.
(19) Grese, T. A.; Sluka, J . P.; Bryant, H. U.; Cullinan, G. J .;
Glasebrook, A. L.; J ones, C. D.; Matsumoto, K.; Palkowitz, A.
D.; Sato, M.; Termine, J . D.; Winter, M. A.; Yang, N.; Dodge, J .
A. Molecular determinants of tissue selectivity in estrogen
receptor modulators. Proc. Natl. Acad. Sci. U.S.A. 1997, 94,
14105-14110.
(13) The binding pocket of ERR and ERâ differs by only two sets of
amino acids: Leu 384/Met 354 and Met 421/Ile 391, respectively.
Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.;
Thorsell, A. G.; Engstrom, O.; Ljunggren, J .; Gustafsson, J . A.;
Carlquist, M. Structure of the Ligand-Binding Domain of
Oestrogen Receptor Beta in the Presence of a Partial Agonist
and a Full Antagonist. EMBO J . 1999, 18, 4608-4618.
(14) Compound 3 exhibited no oral bioavalibility in female Sprague-
Dawley rats dosed at 2 mpk. In contrast, 4 was markedly
improved; F ) 31%. As observed with lasofoxifene,15 the active
enantiomer 4-D exhibited greater oral bioavailability than 4-L:
F ) 62% vs F ) 11%, respectively.
(20) Recent report on an ERR selective compound: Renaud, J .;
Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.; Halleus,
C.; Kallen, J .; Keller, H.; Schaeppi, J .; Stark, W. Estrogen
Receptor Modulators: Identification and Structure-Activity
Relationships of Potent ERR-Selective Tetrahydroisoquinoline
Ligands. J . Med. Chem. 2003, 46, 2945-2957.
(15) Rosati, R. L.; DaSilva J ardine, P.; Cameron, K. O.; Thompson,
D. D.; Ke, H. Z.; Toler, S. M.; Brown, T. A.; Pan, L. C.;
Ebbinghaus, C. F.; Reinhold, A. R.; Elliot, N. C.; Newhouse, B.
J M034243O