Octahydrophenanthrene-2,7-diol Analogues as dissociated glucocorticoid receptor agonists: Discovery and lead exploration

Article abstract of DOI:10.1021/jm801512v

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepre

Full text of DOI:10.1021/jm801512v

J. Med. Chem. 2009, 52, 1731–1743
1731
Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists:
Discovery and Lead Exploration
Ralph P. Robinson,* Leonard Buckbinder, Amber I. Haugeto, Patricia A. McNiff, Michele L. Millham, Matthew R. Reese,
Jean F. Schaefer, Yuriy A. Abramov, Jon Bordner, Yves A. Chantigny, Edward F. Kleinman, Ellen R. Laird,
Bradley P. Morgan, John C. Murray, Eben D. Salter, Matthew D. Wessel, and Sue A. Yocum
Pfizer Global Research & DeVelopment, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
ReceiVed December 1, 2008
As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a
pathway-selective or “dissociated” agonist of the glucocorticoid receptor (GR), retaining the potent activity
that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression)
but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay).
With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2
were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to
be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction
of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Chart 1
Introduction
Synthetic glucocorticoid agonists (glucocorticoids) are the
most effective anti-inflammatory drugs available. The biological
effects of this drug class, and the endogenous adrenal hormone
cortisol, are mediated by the glucocorticoid receptor (GRa), a
member of the nuclear hormone receptor gene family. Despite
being highly efficacious, long-term glucocorticoid therapy is
severely limited by debilitating side effects including diabetes
and osteoporosis.
Inhaled administration of rapidly inactivated glucocorticoids
(e.g., fluticasone propionate) has led to improvements in
therapeutic index by minimizing systemic exposure. Unfortu-
nately, this strategy is limited to use in topical indications and
is not applicable to arthritis and other systemic inflammatory
conditions. An exciting and potentially more general approach
to attenuating the side effects associated with GR-based therapy
has arisen from new understanding regarding pathways involved
in glucocorticoid signaling.
As is the case with agonists of other nuclear hormone
receptors, glucocorticoids activate transcription of some genes
while concurrently repressing transcription of others. In the
transrepression pathway, gene transcription is down-regulated
via protein-protein binding interactions of monomeric GR/
ligand complexes with various transcription factors (e.g., NFκB
and AP1). In the transactivation pathway, gene transcription is
stimulated by binding of dimeric GR/ligand complexes directly
to DNA.
receptor conformations, favor pathways for transrepression over
those for transactivation.1-3
Several classes of compounds have been reported in the
literature to possess the profile of such a pathway-selective or
“dissociated” agonist of GR.1,4 The best characterized is a series
of benzopyrano[3,4-f]quinoline derivatives, for example, (S)-
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propen-1-yl)-1H-
[1]benzopyrano[3,4-f]quinoline (AL-438), that exhibit anti-
inflammatory efficacy in vivo with decreased GR mediated side
effects.3,5 Confidence in the approach has been further strength-
ened by studies with a mouse expressing a GR mutant that
selectively abolishes GR DNA-mediated activity.6
Screening our collection of analogues of the previously
reported GR antagonist 17 led to the identification of 2 (Chart
1), a high affinity nonsteroidal ligand of GR (IC50 ) 6.2 nM)
exhibiting potent transrepression activity as measured by
inhibition of IL-1 stimulated expression of endogenous pro-
inflammatory genes in human chondrosarcoma cells (SW-1353).
In these assays, 2 suppressed induction of IL-8 (controlled in
part by the transcription factor NFκB) with an IC50 ) 34 nM,
achieving 75% the maximal effect of dexamethasone (75% max
dex). Similarly, MMP-13 expression (controlled in part by AP1)
was inhibited with an IC50 of 14 nM (79% max dex). In both
cases, the functional activity of 2 could be reversed by
co-incubation with mifepristone (RU-486), a potent GR antagonist.
At this stage, the ability of 2 and analogues to signal via
transactivation was assayed in SW1353 cells stably transfected
with the glucocorticoid-responsive mouse mammary tumor virus
(MMTV) promotor8 and the luciferase reporter. In this well-
established system, 2 showed appreciably reduced maximal
transactivation activity (8.5%) relative to dexamethasone (100%).
The beneficial effects of glucocorticoids are, for the most part,
mediated via transrepression of pro-inflammatory cytokines and
metalloproteinases, whereas the undesirable effects are mediated
through transactivation of genes linked to gluconeogenesis and
metabolism. Therefore, to identify anti-inflammatory agents that
will have glucocorticoid-like efficacy with reduced side effects,
new GR ligands are sought that, via induction of appropriate
* To whom correspondence should be addressed. Phone: 860-441-4923.
Fax: 860-715-4706. E-mail: ralph.p.robinson@pfizer.com.
a Abbreviations: AR, androgen receptor; ER, estrogen receptor; GR,
glucocorticoid receptor; IL, interleukin; LBD, ligand binding domain; MMP,
matrix metalloproteinase; MMTV, mouse mammary tumor virus; PR,
progesterone receptor.
10.1021/jm801512v CCC: $40.75
2009 American Chemical Society
Published on Web 02/24/2009

1732 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
Scheme 1a
a (a) D,L-methionine, MeSO3H, room temp, ∼18 h; (b) BBr3, CH2Cl2, -78 to 0 °C, 5 h; (c) Li, NH3, THF, -78°; (d) (CH2OH)2, p-TsOH (cat.), toluene,
∆; (e) H2 (3 atm), Pd(OH)2, toluene, 70°C, 16 h; (f) aqueous HCl, THF, room temp, 4.5 h; (g) H2 (3 atm), 10% Pd/C, MeOH, 2 h; (h) PhLi or lithiopropyne,
THF; (i) 4-O2N(C6H4)COCl, aqueous NaOH, acetone, 0°C; (j) O3, MeOH, CH2Cl2, -78°C, ∼1 min, then DMS; (k) aqueous NaOH, THF, room temp; (l)
NaBH4, MeOH, room temp, 20 min; (m) O3, MeOH, CH2Cl2, -78°C, ∼1 min, then DMS, then NaBH4.
Selectivity for GR versus other nuclear hormone receptors
was assessed in binding assays for the estrogen (ER), proges-
terone (PR), and androgen (AR) receptors. Although 2 bound
to PR and AR with low affinity (IC50 > 1000 nM), binding to
ERR and ERꢀ was quite significant (IC50 of 93 and 250 nM,
respectively).
at -78 °C. These conditions invariably led to formation of
∼30% of the corresponding cis B/C ring fused diastereoisomer,
which was removed by fractional crystallization or chromatog-
raphy. Because of our particular interest in compounds bearing
an ethyl group at C4a and the difficulty in carrying out
dissolving metal reductions on large scale, an alternative
procedure was developed for the preparation of 12 from 8.12
Thus, reaction of 8 with ethylene glycol and catalytic TsOH in
refluxing toluene gave 16, the product of ketal formation and
migration of the double bond into the B-ring. Subsequent
catalytic hydrogenation of 16 (H2, Pd(OH)2, toluene, 70 °C)
followed by ketal hydrolysis afforded a 3:1 mixture of 12 and
the corresponding cis ring-fused diastereomer. Catalytic hydro-
genation of the allyl group of 14 yielded ketone 15.
Addition of lithiopropyne to 14 afforded 2 with good
diastereoselectivity. Likewise, lithiopropyne additions to 11-13
and 15 provided 17-20, respectively (Table 1). Exemplified
by the addition of phenyllithium to provide 25 (Table 2),
alternative C2 substituents in the C4a ethyl series could be
obtained by addition of other organometallic reagents to ketone
12.13 For compounds 18 and 25, as well as for compounds 32
and 42 described below, structural assignments were confirmed
by X-ray crystallography.
Herein we describe aspects of our work aimed at defining
the in vitro structure-activity relationships around 2. Our efforts
were guided by a desire to improve the attractiveness of this
compound as a lead for discovery of an orally administered
pathway-selective GR modulator. At the outset, we were
especially interested in finding acceptable replacements for the
C4a allyl, C2 propynyl, and C7 phenolic hydroxyl groups. The
first two were viewed as being potentially susceptible to
oxidative metabolism leading to reactive metabolites. Also, the
reactivity of these functional groups under a variety of oxidizing
and reducing reaction conditions would likely limit the scope
of chemistry that could be carried out to prepare analogues.
Replacing the C7 phenolic hydroxyl group would likely reduce
affinity for ER, a receptor that binds phenolic steroids as
endogenous ligands.9 Since 2 is relatively lipophilic (clogP )
4.6), we also sought to lower its lipophilicity by introducing
additional polar functionality.10
Several analogues were obtained by modification of the C4a
or C7 side chains (R4a and R7) of initial targets. The C4a
hydroxymethyl analogue 21 was obtained from 19 in four steps
including selective ozonolysis of the corresponding C7 4-ni-
trobenzoyl derivative (Scheme 1).14 The C4a 2-hydroxyethyl
analogue 22 was obtained in a similar manner from 2. Selective
alkylation (R7Cl, NaH, THF/DMF) provided the C7 4-pyridyl-
methyl ether 23 and the C7 (2-methyl-2-pyridyl)methyl ethers
24, 26, 31, and 33 from the corresponding phenols (Tables 1
and 2).
Analogues of 18 and 25 bearing an R-OH group at C3 or C4
(30, 32, 36, and 42) were prepared as shown in Schemes 2 and
3. Bromination of 12 using phenyltrimethylammonium perbro-
mide (THF, -78 to 0 °C) regio- and stereoselectively gave the
Chemistry
All compounds were prepared starting from the enones 3-5
(Scheme 1), prepared in high enantiomeric purity from 6-meth-
oxy-2-tetralone according to procedures analogous to those
described previously for the synthesis of 6.7 In the cases of 3
and 4 cleavage of the 7-methoxy group took place in a
straightforward manner using D,L-methionine in methanesul-
phonic acid,11 giving 7 and 8. However, in the case of the allyl
enone 5, these conditions yielded enone 9 through double bond
isomerization. This side reaction was not observed when BBr3/
CH2Cl2 was employed, which allowed the preparation of 10.
Reduction of enones 7-10 to the corresponding ketones
11-14 was carried out using lithium metal in liquid ammonia

Dissociated Glucocorticoid Receptor Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1733
Table 1. C2 Propynyl Analogues
binding IC50 (nM)a
transrepression MMP-13a,b transactivation MMTVa
R7
R4a
R
GR
6.2
17
5.6
3.5
1.5
>103
>103
3
ERR
ERꢀ
AR
PR
IC50 nM (% max dex)
(% max dex)
2
H
H
H
H
H
H
H
allyl
Me
Et
H
H
H
H
H
H
H
H
H
93
250
>103 1100
14 (79)c
>5000
14 (86)c
>5000
>5000
8.5
0.3
6.4
1.6
0.8
17
18
19
20
21
22
89
580
420
2600
CHdCHMe
n-Pr
CH2OH
(CH2)2OH
Et
23 CH2-(4-py)
670
3500
31 (88)
6.3 (90)
63 (79)
15 (84)c,e
14.6
18.4
12.7
18
24 CH2-(2-Me-3-py) Et
30 Et
31 CH2-(2-Me-3-py) Et
36 Et
2.3
>104 >104 880
H
3-R-OH 35
3-R-OH 3.3d
4-R-OH 360
>104 >104 >104 >104
>104 >104 >104 >104
>104 >104 >104
H
a n ) 1 (dose response curves run in triplicate) except where otherwise noted. b IC50: concentration of test compound that inhibits IL-1-induced MMP-13
production by 50%. c Inhibition reversed by coincubation with RU-486. d n ) 2 (IC50 values of 3.0 and 3.5 nM). e n ) 2 (IC50 values of 13 and 16 nM).
Table 2. C2 Phenyl Analogues
binding IC50 (nM)a
transrepression MMP-13a,b
IC50 nM (% max dex)
transactivation MMTVa
(% max dex)
R7
R3
X
GR
ERR
ERꢀ
AR
PR
25
26
32
33
42
48
H
H
H
R-OH
R-OH
ꢀ-OH
R-OH
OH
OH
OH
OH
OH
H
21
6
2.5
1.5
3.8
1.3
>5000
0.9
0
6.2
6.3
2.3
5.8
CH2-(2-Me-3-py)
H
CH2-(2-Me-3-py)
H
H
1500
3400
660
>104
>104
750
140 ( 60 (67)c,d
38 (78)c,e
5000f
>104
>104
>103
1100
a n ) 1 (dose response curves run in triplicate) except where otherwise noted. b IC50: concentration of test compound that inhibits IL-1-induced MMP-13
production by 50%. c Inhibition reversed by co-incubation with RU-486. d n ) 7. e n ) 2 (IC50 values of 25 and 50 nM). f n ) 2 (47% and 58% inhibition
at 5000 nM).
Scheme 2a
Installation of a 4S-hydroxyl group to obtain 36 was carried
out in a manner similar to that published for the synthesis of
1R,25-dihydoxycholesterol.18 Elimination of HBr from 27
(CaCO3, DMA, 170 °C)19 yielded the ∆3-enone, which was
protected as the tert-butyldimethylsilyl ether 34 (Scheme 3).
Epoxidation (aqueous H2O2, NaOH, MeOH) followed by
reductive epoxide opening (Hg, Al, EtOH, aqueous NaHCO3)
gave the 4S-hydroxyketone 35, which was converted to 36 under
the usual conditions.
As a result of the promising biological profile of compounds
32 and 33 (Table 2), an alternative synthesis of 32 was sought
in order to improve the overall yield and control stereochemistry
a (a) PTAB, THF, -78°C to 0°C, 2.5 h; (b) aqueous K2CO2, acetone,
50°C, 1 h; (c) R2M, THF.
at C2. Although an improved overall yield of 32 was not
attained, an alternative synthesis permitted isolation of 42, the
C3 epimer of 32 (Scheme 3). Addition of phenylmagnesium
bromide to 34 led to stereoselective formation of the allylic
alcohol 37. In agreement with literature reports on the regio-
chemistry of the hydroboration of allylic alcohols,20 treatment
of 37 with BH3 ·THF followed by oxidative workup favored
formation of the corresponding 2,3-diols 38 and 39 as opposed
to the 2,4 diols, which were not detected in the product mixture.
Unfortunately, significant over-reduction also occurred, which
gave rise to the unwanted products 40 and 41. Deprotection of
38 and 39 gave 42 and 32, respectively.
3S bromoketone 27.15 Hydrolysis of 27 (K2CO3/aqueous ac-
etone)16 provided the 3S hydroxyketone 2817 along with small
amounts of the isomeric hydroxyketone 29. Treatment of the
mixture of hydroxyketones with lithiopropyne under the usual
conditions provided a ∼3:2 mixture diastereomeric C2 adducts
as well a small amount of an adduct arising from addition to
29. The desired analogue 30 was easily isolated by flash
chromatography. Similarly, addition of phenyllithium to 28
provided triol 32.

1734 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
Scheme 3a
a (a) CaCO3, DMA, reflux, 2 h; (b) TBDMSCl, imidazole, CH2Cl2, room temp, ∼18 h; (c) 30% aqueous H2O2, NaOH, MeOH, -10°C, ∼18 h; (d) Al/Hg,
aqueous NaHCO3, EtOH, 4 h; (e) LiC≡CMe, -78°C to room temp, ∼18 h; (f) PhMgCl, THF, -78°C to room temp, ∼2 h; (g) BH3 ·THF, THF, 0 °C to
room temp, 4 days; (h) TBAF, AcOH, THF, room temp, 4 h.
Scheme 4a
a (a) PhMgBr, THF, -78°C to room temp, 2 h; (b) KHSO4, toluene, ∆, ∼18 h; (c) TBDMSCl, imidazole, CH2Cl2, room temp, ∼18 h; (d) mCPBA,
CHCl3, room temp, ∼18 h; (e) aqueous H2SO4, DMSO, room temp, ∼18 h, then 60°C, ∼24 h; (f) BF3 ·OEt2, CH2Cl2, -78°C, 20 min; (g) NaBH4, MeOH,
-78° to room temp; (h) TBAF, AcOH, THF, 2 h.
Similarly, in the course of further exploration of routes to
32, a synthesis of 48 (the analogue of 32 in which the C2 OH
is replaced with H) was developed (Scheme 4). Addition of
phenylmagnesium bromide to 12 followed by elimination using
KHSO4 in hot toluene provided olefin 43.21 Epoxidation of 43
using mCPBA took place exclusively from the R face, giving
44. Compound 32 was not detected following exposure of 44
to aqueous acid in DMSO, which instead yielded the diol 45
and ketone 46, both having an equatorial (ꢀ) phenyl substituent.
In contrast, treatment of 44 with BF3 ·OEt2 in CH2Cl2 at -78
°C cleanly provided ketone 47, which was treated with NaBH4
and deprotected to give 48. We attribute the formation of 46
under aqueous conditions to acid-catalyzed enolization of 47
initially formed by stereospecific 1,2-hydride shift.
homology model of the GR ligand binding domain (LBD) based
on the crystal structure of PR with bound dexamethasone.22 In
the most favorable orientation (Figure 1), the A, B, and C rings
of 2 align well with the corresponding rings of dexamethasone
(not shown). Interestingly, the C4a allyl substituent projects
toward helix 5 and there is no direct interaction with helix 12,
the conformation of which is important in determining GR
agonism versus antagonism.23 The homology model suggests
that the C7 hydroxyl group plays a role similar to that of the A
ring carbonyl function of dexamethasone, forming hydrogen
bonds with Arg611 and Gln570. Considering that large groups
at C7 (as in 23 and 24, vide infra) are often well tolerated, we
postulate that such groups may protrude into a surface cleft
formed by reorientation of the polar and solvent-accessible
Gln570 and Arg611 side chains.
Discussion
The C4a allyl substituent of 2 was expected to be reactive
under various reductive and oxidative conditions and is installed
early in the synthesis. Thus, before commitment of resource to
To help guide target design and understand structure-activity
relationships with respect to GR binding, 2 was docked into a

Dissociated Glucocorticoid Receptor Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1735
Figure 1. Compound 2 docked into the GR ligand binding domain
(homology model).
producing bulk intermediates for exploration of other structural
modifications, identifying a more chemically stable replacement
for the allyl group was our first priority in exploring
structure-activity relationships around 2.
Figure 2. Compound 30 docked into the GR ligand binding domain
(homology model).
hydrophobic nature of the surrounding area of the binding
pocket. Nevertheless, since functionalization of the C4a group
was relatively straightforward, we prepared the C4a hydroxym-
ethyl and 2-hydroxyethyl analogues 21 and 22, respectively.
Neither compound showed appreciable GR binding at 5 µM
(Table 1).
The most easily obtained C4a variant of 2 was the corre-
sponding n-propyl analogue (20). Unfortunately, despite having
potent binding to GR, this compound lacked activity in the IL-1
induced MMP-13 assay (Table 1). This was also the case for
the C4a methyl and 1-propenyl analogues (17 and 19, respec-
tively), indicating that transrepression activity within the series
is very sensitive to minor structural changes at the C4a position.
In contrast, the C4a ethyl analogue 18 showed a profile quite
similar to that of 2.24 On the basis of this favorable result and
the relative chemical inertness of the ethyl group, subsequent
exploration of the series focused predominantly on analogues
bearing ethyl at the C4a position.
Similar to 2, 18 showed appreciable affinity for ERR and
ERꢀ (IC50 of 89 and 580 nM, respectively). Fortunately,
conversion of the C7 hydroxyl to ether derivatives provided
compounds with significantly improved selectivity for GR.
Pyridylmethyl ether derivatives such as 23 and 24 had especially
We next explored the possibility of introducing polarity into
the C-ring by preparing the C3R hydroxyl and C4R hydroxyl
analogues 30 and 36, respectively. This effort was inspired by
the structural analogy to corticosteroids, which require a
hydroxyl group at position 11ꢀ in the C-ring (corresponding to
C4R in our series), as well as the GR LBD homology model,
which revealed possibilities for a C3 or C4 hydroxyl substituent
to form hydrogen bond interactions with the polar amino acid
side chain of Asn564 (Figure 2). The C4R hydroxyl analogue
36 bound GR weakly (IC50 ) 360 nM). However, the C3R
hydroxyl isomer (30) retained much of the GR-related activity
of the parent compound 18 (Table 1), and despite an unmasked
hydroxyl group at C7, the compound showed no appreciable
affinity for ER. Compound 31, the (3-methyl-2-pyridyl)methyl
derivative of 30, displayed improved activity with respect to
GR binding and transrepression. Its activity profile resembled
closely that of 24, the corresponding analogue unfunctionalized
at C3. Thus, we achieved our objective of introducing additional
polar functionality onto the tricyclic skeleton to reduce lipo-
philicity (e.g., 30, clogP ) 3.7 versus 18, clogP ) 4.6; 31, clogP
) 5.0 versus 24, clogP ) 5.9) without negatively impacting
the biological profile.
attractive profiles (e.g., 24, ERR IC50 >10000 nM; ERꢀ IC50
10000 nM; GR IC50 ) 2.3 nM).
>
Having established that ethyl is an acceptable substituent at
the C4a position, we next concentrated on finding suitable
replacements for the 1-propynyl group at C2. A particular
concern with alkyne functionality was the potential for formation
of reactive species arising from epoxidation of the C-C triple
bond. Inspection of the 2-ligated GR LBD homology model
showed that the propyne group projects into a hydrophobic
pocket formed by residues M560, M639, M646, I559, I629,
L563, L732, and F623 (Figure 1, select residues shown). For
this reason, we prepared numerous analogues with lipophilic
C2 groups varying in both size and rigidity (e.g., alkyl, alkenyl,
arylmethyl, aryl, heteroaryl). Exemplified by 25 and its ether
derivative 26 (Table 2), relatively small changes in structure at
C2 resulted in loss of transrepression and, in many cases,
significant attenuation of GR binding affinity as well.
In parallel with our efforts to find an acceptable substitute
for the C2 propynyl group, we began an investigation into the
possibility of introducing additional polar functionality in order
to lower the overall lipophilicity of the series. This was driven
in large part by the observation that poor aqueous solubility
often resulted from derivatization of the C7 hydroxyl group
(necessary to increase selectivity over ER) and the high clogP
values for compounds such as 24 (clogP ) 5.9). The GR LBD
homology model with bound 2 suggested that polar functionality
on the C4a side chain would not be favored because of the
Although the route to 30 was low-yielding, it nonetheless
allowed the preparation of additional C3R hydroxyl analogues
such as C2 phenyl analogue 32 (Table 2). Strikingly, in contrast
to all other non-alkyne C2 analogues yet prepared, 32 unexpect-
edly inhibited IL-1 induced MMP-13 expression (IC50 ) 140
nM, 67% max dex), albeit somewhat attenuated relative to 18
and 30. Again, activity in the transrepression assay was increased
through preparation of the corresponding (3-methyl-2-pyridyl)-
methyl derivative 33 (IC50 ) 38 nM, 78% max dex), which
retained a low propensity for transactivation in the MMTV assay
(6% dex). Additionally, 33 showed high selectivity for GR over
the other nuclear hormone receptors assayed (binding IC50 of
>1000 nM). In contrast to 32, the C3ꢀ epimer 42 failed to show
transrepression activity despite having high affinity for GR.
Compound 48, lacking the C2ꢀ hydroxyl, bound GR potently
but showed only very weak activity in the transrepression assay.

1736 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
Binding to GR is quite tolerant of C2 and C4a side chain
variation, in contrast to transrepression activity, which is much
less so. Introduction of a C3R hydroxyl group restored tran-
srepression activity to C2 phenyl analogues, obviating the
requirement for a 1-propynyl group at this position. Thus, as
demonstrated by our discovery of compounds 32 and 33, we
were successful in preparing analogues of 2 in which the allyl
and propynyl side chains are replaced with groups likely to be
more chemically stable and less likely to produce toxic
metabolites. At the same time, selectivity for binding GR versus
binding ER was increased. Although their follow-up is beyond
the scope of this paper, these analogues have proven key to
identification of drug-candidate-quality GR modulators for the
treatment of inflammation.25
Experimental Section
Chemistry. Reagents were purchased commercially and used
without further purification unless otherwise indicated. Reactions
were performed under a nitrogen atmosphere, magnetically stirred,
and run at room temperature except where otherwise indicated.
Analytical thin-layer chromatography (TLC) was carried out using
Merck silica gel 60 F254 plates on which compounds were visualized
using ultraviolet (UV) light and ceric ammonium molybdate stain.
Chromatography was performed on Biotage Flash 25 or Flash 40
columns (Cyax Corp.) under low pressure. Preparative HPLC was
carried out on a Shimadzu Discovery VP instrument using a Waters
Xterra Prep MS C18, 5 µm, 30 mm × 50 mm column and eluting
with a 5-100% gradient of 0.1% formic acid in acetonitrile and
0.1% formic acid in water.
Figure 3. Overlaid X-ray crystal structures of compounds 32 (blue)
and 42 (orange).
With the discovery of compounds 32 and 33, we achieved
our initial goal of finding replacements for the C4a allyl and
C2 propynyl groups of 2, at the same time improving GR
selectivity and maintaining specificity for transrepression over
transactivation. Furthermore, the introduction of additional polar
functionality allowed the C7 hydroxyl to be derivatized, thus
counteracting the potential for increased lipophilicity and
decreased aqueous solubility when doing so.
On the basis of the GR LBD homology model, the ability of
the C3R hydroxyl to hydrogen-bond to Asn564 may be a factor
in promoting the unexpected transrepression activity elicited by
compounds 32 and 33. However, this does not explain why, in
the C2 propyne series, agonist activity is independent of the
presence of a C3R hydroxyl. Alternatively, the role of the C3
hydroxyl may be to help populate conformations that are
preferred for transrepression. X-ray crystallography and quantum
mechanical calculations indicate that differences in conforma-
tional preference do arise upon introduction of the C3R hydroxyl
group, although the changes are relatively minor. Thus, in the
X-ray crystal structures of 25 and 42, the orientations of the
C2 phenyl group are identical, the C2-C3 single bond nearly
lying in the plane described by the C2 phenyl ring. However,
in the X-ray structure of 32, the phenyl ring is tilted about 30°
relative to that of 42 (Figure 3). Quantum mechanical calcula-
tions indicate that the barrier to free phenyl ring rotation (ER)
is about 1 kcal/mol for compounds 25 and 42. In contrast, the
phenyl ring in 32 is less free to rotate (ER ) 4 kcal/mol) as a
result of interaction with the C3 hydroxyl substituent.
Enantiomeric excess (ee) determinations were carried out by
chiral HPLC on a Chiralcel OJ column, eluting with 2-propanol/
hexane (1% diethylamine) and detecting by UV at 214 nm. 1H NMR
spectra were recorded in CDCl3 or DMSO-d6 solutions on a Varian
Unity 400 or 500 MHz spectometer. Chemical shifts are reported
in parts per million (δ) relative to residual CHCl3 (7.24 ppm) or
DMSO (2.49 ppm) as internal reference. Coupling constants (J)
are reported in hertz (Hz). The peak shapes are denoted as follows:
s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Low
resolution mass spectra (LCMS) were recorded by positive and
negative electrospray ionization (ESI) using a Waters/Micromass
ESI/MS model ZMD/LCZ mass spectrometer equipped with Gilson
215 liquid handling system and Hewlett-Packard 1100 diode array
detector. Elemental analyses were performed by Quantitative
Technologies, Inc., Whitehouse, NJ, and are within (0.4% of the
calculated values unless stated otherwise. X-ray crystal structures
were collected on a Bruker APEX or a Siemens P4 diffractometer.
1-Ethyl-6-methoxy-3,4-dihydro-1H-naphthalen-2-one. A solu-
tion of 6-methoxy-2-tetralone (120.55 g, 0.684 mol) and pyrrolidine
(61 mL, 0.685 mol) in toluene (1.7 L) was heated to reflux using
a Dean-Stark trap for 3 h. The reaction mixture was cooled to
room temperature and concentrated to a solid. Ethyl iodide (121
mL, 1.51 mol) and MeOH (1.2 L) were added. The resulting
solution was heated at reflux overnight and then concentrated. A
solution of AcOH (120 mL) and NaOAc (120 g) in H2O (240 mL)
was added to the residue, and the resulting mixture was heated at
reflux for 2 h. The mixture was cooled and extracted several times
with Et2O. The combined organic layers were washed twice with
aqueous 1 M HCl, twice with aqueous 1 M NaOH, and once with
brine. After the solution was dried (MgSO4), the solvent was
evaporated to afford the title compound as an oil, 121.8 g. 1H NMR
(CDCl3): δ 7.06 (d, J ) 8.3 Hz, 1 H), 6.81-6.78 (m, 2 H), 3.83 (s,
3 H), 3.30 (apparent t, J ) 6.7 Hz, 1 H), 3.18-3.12 (m, 1 H),
3.00-2.94 (m, 1 H), 2.68-2.62 (m, 1 H), 2.58-2.49 (m, 1 H),
1.92-1.86 (m, 2 H), 0.91 (t, J ) 7.3 Hz, 3 H). LCMS: m/z 204
[M]+.
Conclusion
Compounds derived from the nonsteroidal octahydrophenan-
threne template (e.g., 1) have been previously described as
potent, selective GR receptor antagonists. As exemplified by 2,
close-in analogues of 1 exhibit the profile of a pathway-selective
or “dissociated” agonist of GR, retaining the potent activity that
glucocorticoids have for transrepression (as measured by inhibi-
tion of IL-1 induced MMP-13 expression) but showing an
attenuated capacity for transactivation (as measured in the
MMTV luciferase reporter assay).
To guide design of compounds having improved structural
and physicochemical characteristics, a GR ligand binding
domain homology model was developed on the basis of a crystal
structure of the progesterone receptor. This model proved to
be very useful, especially in the design of analogues bearing
an additional hydroxyl group to lower overall lipophilicity.
(1S,9S)-Ethyl-10-hydroxy-5-methoxy-10-methyl-tricyclo[7.3.1.02,7]-
trideca-2,4,6-trien-13-one. A solution of 1-ethyl-6-methoxy-3,4-
dihydro-1H-naphthalen-2-one (121.8 g, 0.592 mol) and freshly
distilled (S)-(-)-R-methylbenzylamine (72 g, 0.592 mol) in toluene

Dissociated Glucocorticoid Receptor Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1737
(600 mL) was heated at reflux overnight using a Dean-Stark trap
to collect water. Roughly half of the toluene was then distilled off,
and freshly distilled methylvinylketone (4.39 g, 0.626 mol) was
added dropwise. The solution was stirred at room temperature for
2 h and then heated in an oil bath at 45 °C overnight. The mixture
was cooled in an ice bath, and aqueous 10% H2SO4 was added.
After it was stirred at room temperature for 2 days, the solution
was extracted three times with EtOAc. The combined organic layers
were washed with H2O, washed with brine, dried (MgSO4), and
concentrated to afford an oil. The title compound (59.6 g) was
isolated by chromatography, eluting with 15% EtOAc/hexanes
2.93-2.90 (m, 2 H), 2.71-2.70 (m, 1 H), 2.50-1.50 (m, 10 H),
0.81 (t, J ) 7.8 Hz, 3 H). LCMS: m/z 245 [MH]+. Anal. (C16H20O2)
C, H.
(4aS)-4a-Allyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenanthren-
2-one (5). This intermediate was prepared in a manner analogous
to the preparation of 4 starting from 6-methoxy-2-tetralone and allyl
1
bromide, ee ) 97.9%. H NMR (CDCl3): 7.12 (d, J ) 8.5 Hz, 1
H), 6.80 (dd, J ) 2.7, 8.5 Hz, 1 H), 6.63 (d, J ) 2.7 Hz, 1 H), 5.95
(s, 1 H), 5.67-5.55 (m, 1 H), 5.03-4.96 (m, 2 H), 3.80 (s, 3 H),
3.02-2.95 (m, 1 H), 2.90-2.60 (m, 5 H), 2.58-2.40 (m, 3 H),
2.08-1.99 (m, 1 H). LCMS: 269 [MH]+. Anal. (C18H20O2) C, H.
(4aS)-4a-Allyl-7-hydroxy-4,4a,9,10-tetrahydro-3H-phenanthren-
2-one (10). Boron tribromide (10.6 mL, 112 mmol) was added
dropwise to a solution of 5 (15.0 g, 55.9 mmol) in CH2Cl2 (350
mL) at -78°. The mixture was allowed to warm to 0 °C over 5 h
and was then poured into ice-water. Solid NaHCO3 was carefully
added to neutralize the mixture, which was then extracted with
EtOAc. The organic extract was washed with brine, dried (MgSO4),
and concentrated. Compound 10 (11.0 g, 53%) was isolated by
1
followed by 21% EtOAc/hexanes. H NMR (CDCl3): δ 7.04 (d, J
) 8.7 Hz, 1 H), 6.80 (dd, J ) 2.5, 8.7 Hz, 1 H), 6.61 (d, J ) 2.5
Hz, 1 H), 3.79 (s, 3 H), 3.32 (dd, J ) 7.1, 17.8 Hz, 1 H), 3.08 (d,
J ) 17.8 Hz, 1 H), 2.50 (d, J ) 7.1 Hz, 1 H), 2.20-2.05 (m, 2 H),
1.77-1.68 (m, 1 H), 1.59 (br s, 1 H), 1.52-1.35 (m, 3 H), 1.34 (s,
3 H), 0.82 (t, J ) 7.3 Hz, 3 H). LCMS: m/z 275 [MH]+.
(4aR)-4a-Ethyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenan-
thren-2-one (4). A solution of 59.6 g (0.217 mol) of (1S,9S)-ethyl-
10-hydroxy-5-methoxy-10-methyl-tricyclo[7.3.1.02,7]trideca-2,4,6-
trien-13-one in MeOH (300 mL) was added dropwise to 1 M
NaOMe in MeOH (250 mL). The mixture was heated at reflux for
3 h and then cooled to room temperature. The mixture was
neutralized with AcOH and concentrated. The residue was dissolved
in EtOAc and washed sequentially with aqueous saturated NaHCO3,
H2O, and brine. After the solution was dried (MgSO4), the solvent
1
chromatography, eluting with 5-10% EtOAc/CH2Cl2. H NMR
(CDCl3): δ 7.14 (d, J ) 8.5 Hz, 1 H), 6.72 (dd, J ) 2.7, 8.5 Hz,
1 H), 6.58 (d, J ) 2.7 Hz, 1 H), 5.94 (s, 1 H), 5.62-5.54 (m, 1 H),
5.03-4.98 (m, 2 H), 4.85 (br s, 1 H), 2.95-2.91 (m, 1 H),
2.85-2.63 (m, 5 H), 2.53-2.40 (m, 3 H), 2.08-1.99 (m, 1 H).
LCMS: 255 [MH]+. Anal. (C17H18O2 ·0.25 H2O) C, H.
(4aS,10aR)-4a-Allyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-1H-
phenanthren-2-one (14). A three-neck round-bottom flask was
equipped a dry ice reflux condenser and a mechanical stirrer.
Ammonia (400 mL) was condensed into the flask at -78 °C. To
this flask was added approximately 0.08 g (11.5 mmol) of Li wire
to obtain a dark-blue solution. A solution of 10 (10.5 g, 41.3 mmol)
in THF (100 mL) was slowly added to the mixture, keeping the
mixture dark-blue. Just before dissipation of the blue color was
anticipated, more Li (about 0.08 g, 11.5 mmol) was added to
maintain the blue color. The process was repeated until a total
amount of 0.6 g (86.5 mmol) Li had been added. The mixture was
stirred an additional 30 min after addition of the enone was complete
and was quenched by dropwise addition of excess aqueous saturated
NH4Cl. The mixture was allowed to warm to room temperature,
and the NH3 was allowed to evaporate. The residue was taken up
in H2O and extracted twice with EtOAc. The combined organic
layers were washed with brine, dried (MgSO4), and concentrated.
The crude product was triturated with Et2O and filtered to collect
1
was evaporated to afford 4 as a tan solid, 55 g, ee ) 98.9%. H
NMR (CDCl3): δ 7.15 (d, J ) 8.7 Hz, 1 H), 6.77 (dd, J ) 2.9, 8.7
Hz, 1 H), 6.62 (d, J ) 2.9 Hz, 1 H), 5.91 (s, 1H), 3.77 (s, 3 H),
2.99-2.93 (m, 1 H), 2.85-2.34 (overlapping m, 6 H), 2.04-1.87
(m, 3 H), 0.79 (t, J ) 7.6 Hz, 3 H). LCMS: m/z 257 [MH]+.
(4aR)-4a-Ethyl-7-hydroxy-4,4a,9,10-tetrahydro-3H-phenan-
thren-2-one (8). To a well-stirred solution of 4 (55 g, 0.214 mol)
in methanesulfonic acid (890 mL) was added, in portions, D,L-
methionine (106.7 g, 0.715 mol). The mixture was stirred overnight,
poured into ice, and stirred for an additional 30 min. The
precipitated solid was collected by filtration and then dissolved in
EtOAc. The resulting solution was washed with aqueous saturated
NaHCO3 and brine. After the solution was dried (MgSO4), the
solvent was evaporated to afford a red semisolid. This was triturated
with Et2O and filtered to collect 8 as a yellow solid (34 g, 66%).
1H NMR (CDCl3): δ 7.14 (d, J ) 8.3 Hz, 1 H), 6.76 (dd, J ) 2.6,
8.3 Hz, 1 H), 6.62 (d, J ) 2.6 Hz, 1 H), 5.97 (s, 1H), 3.00-2.95
(m, 1 H), 2.86-2.38 (overlapping m, 6 H), 2.08-1.90 (m, 3 H),
0.84 (t, J ) 7.3 Hz, 3 H). LCMS: m/z 243 [MH]+. Anal. (C16H18O2)
C, H.
1
14 as a tan solid (5.22 g, 49%). H NMR (CDCl3): δ 7.05 (d, J )
8.3 Hz, 1 H), 6.62-6.58 (m, 2H), 5.72-5.62 (m, 1 H), 5.08-5.01
(m, 2 H), 4.73 (br s, 1 H), 2.91-2.88 (m, 2 H), 2.63-2.28 (m, 7
H), 2.11-2.03 (m, 1 H), 1.95-1.84 (m, 1 H), 1.66-1.56 (m, 2 H).
(4aR)-4a-Methyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenan-
thren-2-one (3). This intermediate was prepared in a manner
analogous to the preparation of 4 starting from 6-methoxy-2-
tetralone and methyl iodide. 1H NMR (CDCl3): δ 7.20 (d, J ) 8.7
Hz, 1 H), 6.80 (dd, J ) 2.5, 8.7 Hz, 1 H), 6.60 (d, J ) 2.5 Hz, 1
H), 5.88 (s, 1 H), 3.78 (s, 3 H), 2.96-2.94 (m, 1 H), 2.89-2.82
(m, 1 H), 2.75-2.65 (m, 2 H), 2.54-2.47 (m, 2 H), 2.36-2.31
(m, 1 H), 2.03 (td, J ) 4.4, 14.5 Hz, 1 H), 1.54 (s, 3 H). LCMS:
m/z 243 [MH]+. Anal. (C16H18O2) C, H.
4a-(R)-Ethyl-7-hydroxy-3,4,4a,9-tetrahydro-1H-phenanthren-
2-one Ethylene Ketal (16). A mixture of 8 (156 g, 0.644 mol),
ethylene glycol (180 mL, 3.22 mol), p-TsOH·H2O (10 mg), and
toluene (10 L) was heated to reflux for 16 h using a Dean-Stark
apparatus. The mixture was cooled to room temperature, concen-
trated, and dissolved in EtOAc. The resulting solution was washed
with H2O, washed with brine, dried (K2CO3), and concentrated.
Compound 16 (154 g, 84%) was isolated as a low melting solid by
chromatography, eluting with 30% EtOAc/hexanes. LCMS: m/z 287
[MH]+.
(4aR)-7-Hydroxy-4a-methyl-4,4a,9,10-tetrahydro-3H-phenan-
thren-2-one (7). This intermediate was obtained by demethylation
of 3 using a procedure analogous to the preparation of 8.
Recrystallization was from hot EtOAc with a trace of MeOH, ee
(4aR,10aR)-4a-Ethyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-
1H-phenanthren-2-one (12). To a suspension of 20% Pd(OH)2/C
(25.3 g) in toluene (2.53 L) was added 16 (253 g, 0.883 mol). The
resulting mixture was hydrogenated at 3 atm for 48 h at 65 °C. It
was then cooled to room temperature, filtered, and concentrated.
The residue was chromatographed, eluting with 30% EtOAc/
hexanes. Fractions containing the intermediate hydrogenation
product were concentrated and dissolved in THF (1 L). Aqueous 1
M HCl (1 L) was added, and the resulting mixture was stirred at
room temperature for 2 h. The mixture was extracted with Et2O,
and the extracts were washed with brine, dried (MgSO4), and
concentrated. The title compound (115 g, 54%) was isolated by
chromatography (30% EtOAc/hexanes as eluant) and subsequent
1
) 97.2%. H NMR (CDCl3): δ 7.15 (d, J ) 8.3 Hz, 1 H), 6.73
(dd, J ) 2.9, 8.3 Hz, 1 H), 6.56 (d, J ) 2.9 Hz, 1 H), 5.89 (s, 1 H),
2.96-2.90 (m, 1 H), 2.87-2.79 (m, 1 H), 2.74-2.65 (m, 2 H),
2.53-2.47 (m, 2 H), 2.35-2.30 (m, 1 H), 2.03 (td, J ) 4.9, 14.3
Hz, 1 H), 1.53 (s, 3 H). LCMS: m/z 229 [MH]+. Anal. (C15H16O2)
C, H.
(4aR,10aR)-7-Hydroxy-4a-methyl-3,4,4a,9,10,10a-hexahydro-
1H-phenanthren-2-one (11). This intermediate was obtained by
dissolving metal reduction of 7 using a procedure analogous to the
preparation of 14 from enone 10. Recrystallization was from hot
1
recrystallization from 50% EtOAc/hexanes. Mp 169-171 °C. H
NMR (CDCl3): δ 7.11 (d, J ) 8.3 Hz, 1 H), 6.65-6.60 (m, 2H),
1
EtOAc/hexane. H NMR (CDCl3): δ 7.16 (d, J ) 8.7 Hz, 1 H),

1738 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
6.65 (dd, J ) 2.5, 8.7 Hz, 1 H), 6.58 (d, J ) 2.5 Hz, 1 H), 4.90 (br
s, 1 H), 2.88-2.78 (m, 2 H), 2.61-2.27 (m, 5 H), 2.02-1.93 (m,
1 H), 1.82-1.71 (m, 2 H), 1.61-1.55 (m, 1 H), 1.26 (s, 3 H).
LCMS: m/z 231 [MH]+. Anal. (C15H18O2) C, H.
(4aS,10aR)-7-(tert-Butyldimethylsilanyloxy)-4a-ethyl-
4a,9,10,10a-tetrahydro-1H-phenanthren-2-one (34). A solution
of 27(4.0 g, 12.3 mmol) in dimethylacetamide (150 mL) was added
slowly to a refluxing mixture of CaCO3 in dimethylacetamide (100
mL). Heating to reflux was continued for 2 h. The mixture was
cooled, aqueous 1 M HCl was added, and the mixture was extracted
twice with Et2O. The combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The corresponding ∆3-
enone (1.22 g, 41%) was isolated by chromatography, eluting with
(4aS)-7-Hydroxy-4a-(1-propenyl)-4,4a,9,10-tetrahydro-3H-
phenanthren-2-one (9). This intermediate was prepared by treat-
ment of 5 with D,L-methionine and methansulfonic acid using a
procedure analogous to the demethylation of 4 to provide 8. The
title compound was purified by chromatography, eluting with 10%
1
1
5% EtOAc/CH2Cl2. H NMR (CDCl3): δ 7.68 (d, J ) 10.4 Hz, 1
EtOAc/CH2Cl2. H NMR (CDCl3): δ 7.13 (d, J ) 8.3 Hz, 1 H),
H), 7.29 (d, J ) 8.8 Hz, 1 H), 6.72 (dd, J ) 3.1, 8.8 Hz, 1 H), 6.67
(d, J ) 3.1 Hz, 1 H), 6.10 (d, J ) 10. Four Hz, 1 H), 5.90 (br s,
1 H), 2.99-2.91 (m, 2 H), 2.61 (dd, J ) 14.3, 17.9 Hz, 1 H),
2.48-2.39 (m, 2 H), 2.01-1.92 (m, 1 H), 1.85-1.78 (m, 1 H),
1.75-1.70 (m, 1 H), 1.67-1.60 (m, 1 H), 0.88 (t, J ) 7.8 Hz, 3
H).
6.73 (dd, J ) 2.5, 8.3 Hz, 1 H), 6.56 (d, J ) 2.5 Hz, 1 H), 6.00 (s,
1 H), 5.54 (d, J ) 15.4 Hz, 1 H), 5.27 (dq, J ) 6.6, 15.4 Hz, 1 H),
2.90-2.35 (overlapping m, 8 H), 2.07-2.00 (m, 1 H), 1.62 (d, J
) 6.6 Hz, 3 H).
(4aS,10aR)-7-Hydroxy-4a-(1-propenyl)-3,4,4a,9,10,10a-hexahy-
dro-1H-phenanthren-2-one (13). This intermediate was obtained
by dissolving metal reduction of 9 using a procedure analogous to
the preparation of 14 from enone 10. Recrystallization was from
The ∆3-enone (245 mg, 1.01 mmol) was dissolved in CH2Cl2
(20 mL). Imidazole (85 mg, 1.25 mmol) and tert-butyldimethyl-
silylchloride (175 mg, 1.16 mmol) were added, and the mixture
was stirred overnight. The mixture was diluted with CH2Cl2 and
then washed with aqueous 0.5 M citric acid, water, and brine. The
solution was dried (MgSO4) and concentrated to afford 34 as an
1
hot EtOAc. H NMR (CDCl3): δ 7.10 (d, J ) 8.3 Hz, 1 H), 6.63
(dd, J ) 2.5, 8.3 Hz, 1 H), 6.54 (d, J ) 2.5 Hz, 1 H), 5.87 (d, J )
15.4 Hz, 1 H), 5.18 (dq, J ) 6.6, 15.4 Hz, 1 H), 4.95 (br s, 1 H),
2.84-2.64 (overlapping m, 4 H), 2.48-2.43 (m, 1 H), 2.39 (d, J
) 14.5 Hz, 1 H), 2.27 (apparent d, J ) 14.9 Hz, 1 H), 1.99-1.95
(m, 1 H), 1.87-1.77 (m, 2 H), 1.67 (d, J ) 6.6 Hz, 3 H), 1.54-1.49
(m, 1 H). Anal. (C17H20O2) C, H.
1
oil, 322 mg (89%). H NMR (CDCl3): δ 7.67 (d, J ) 10.4 Hz, 1
H), 7.28 (d, J ) 8.3 Hz, 1 H), 6.68 (dd, J ) 2.6, 8.3 Hz, 1 H), 6.64
(d, J ) 2.6 Hz, 1 H), 6.08 (d, J ) 10. Four Hz, 1 H), 2.95-2.90
(m, 2 H), 2.60 (dd, J ) 15.0, 18.6 Hz, 1 H), 2.47-2.41 (m, 2 H),
2.01-1.94 (m, 1 H), 1.84-1.78 (m, 1 H), 1.76-1.70 (m, 1 H),
1.68-1.62 (m, 1 H), 1.00 (s, 9 H), 0.87 (t, J ) 7.8 Hz, 3 H), 0.21
(s, 6 H).
(4aR,10aR)-7-Hydroxy-4a-(1-propyl)-3,4,4a,9,10,10a-hexahy-
dro-1H-phenanthren-2-one (15). A solution of 14 (500 mg, 1.95
mmol) in MeOH (20 mL) was hydrogenated at 3 atm for 2 h. The
mixture was passed through a 0.45 µm nylon filter, and the filtrate
was concentrated to afford 15 (492 mg, 98%) as a white solid. 1H
NMR (CDCl3): δ 7.07 (d, J ) 8.3 Hz, 1 H), 6.62-6.57 (m, 2 H),
2.90-2.86 (m, 2 H), 2.66 (dt, J ) 4.2, 13.3 Hz, 1 H), 2.48 (d, J )
13.7 Hz, 1 H), 2.46-2.40 (m, 2 H), 2.30 (dd, J ) 4.2, 15.4 Hz, 1
H), 2.03-1.85 (overlapping m, 2 H), 1.78-1.71 (m, 1 H),
1.63-1.54 (m, 2 H), 1.43-1.16 (overlapping m, 3 H), 0.85 (t, J )
7.1 Hz, 3 H).
(4R,4aR,10aR)-4a-Ethyl-4,7-dihydroxy-3,4,4a,9,10,10a-hexahy-
dro-1H-phenanthren-2-one (35). A solution of 34 (570 mg, 1.60
mmol) in MeOH (100 mL) was cooled to -10 °C in an ice/salt
bath. Aqueous 5% NaOH (6.4 mL) and then aqueous 30% H2O2
(0.11 mL, 8.0 mmol) were added. The reaction mixture was allowed
to stand in a freezer (-10 °C) overnight. The reaction was quenched
by addition of aqueous 0.5 M citric acid and then partially
concentrated to remove MeOH. The mixture was extracted three
times with EtOAc. The combined extracts were washed with brine,
dried (MgSO4), and concentrated to afford the corresponding 3,4-
epoxide (452 mg, 76%) as a yellow oil. 1H NMR (CDCl3): δ 7.31
(d, J ) 8.3 Hz, 1 H), 6.69 (dd, J ) 2.6, 8.3 Hz, 1 H) 6.63 (d, J )
2.6 Hz, 1 H), 4.19 (d, J ) 4.2 Hz, 1 H), 3.43 (d, J ) 4.2 Hz, 1 H),
2.92-2.86 (m, 2 H), 2.64-2.57 (m, 1 H), 2.50 (dd, J ) 6.2, 19.2
Hz, 1 H), 2.17 (dd, J ) 11.9, 19.2 Hz, 1 H), 1.76-1.48 (series of
m, 4 H), 1.00 (s, 9 H), 0.90 (t, J ) 7.8 Hz, 3 H), 0.21 (s, 6 H).
Strips of Al foil (3.38 g total) were separately dipped in aqueous
2% HgCl2 for 20 s, rinsed with EtOAc and Et2O, and added to a
stirred mixture of the 3,4-epoxide, aqueous NaOH (10 w/v, 5 mL),
and EtOH (50 mL) cooled in an ice/salt bath at -10 °C. The mixture
was stirred at -10 °C for 4 h and then filtered through a pad of
Celite, washing with CHCl3. Brine was added to the filtrate. The
aqueous layer was separated and extracted three times with CHCl3.
The combined CHCl3 layers were dried (MgSO4) and concentrated
to give a yellow oil. Compound 35 (62 mg, 20%) was isolated by
chromatography, eluting with a gradient of 25-50% EtOAc/
(3S,4aR,10aR)-3-Bromo-4a-ethyl-7-hydroxy-3,4,4a,9,10,10a-
hexahydro-1H-phenanthren-2-one (27). To a solution of 12 (1.0
g, 4.1 mmol) in THF (100 mL) at -78 °C was added phenyltri-
methylammonium bromide tribromide (1.57 g, 4.2 mmol) in
portions. The mixture was allowed to stir at -78 °C for 20 min
and then allowed to slowly warm to about room temperature over
0.5 h. Brine was added, and the resulting mixture was extracted
twice with EtOAc. The combined extracts were dried (MgSO4) and
concentrated to give an orange oil. Compound 27 (647 mg, 49%)
was isolated as a white foam by chromatography, eluting with a
1
gradient of 15-50% EtOAc/hexanes. H NMR (CDCl3): δ 7.08
(d, J ) 8.3 Hz, 1 H), 6.64 (apparent d, J ) 8.3 Hz, 1 H), 6.62
(apparent s, 1 H), 4.79 (dd, J ) 5.7, 13.5 Hz, 1 H), 3.28 (dd, J )
5.7, 13.5 Hz, 1 H), 2.94-2.91 (m, 2 H), 2.63-2.61 (m, 2 H),
2.19-2.13 (m, 1 H), 2.08 (t, J ) 13.5 Hz, 1 H), 1.95-1.85 (m, 2
H), 1.72-1.66 (m, 1 H), 1.58-1.52 (m, 1 H), 0.92 (t, J ) 7.8 Hz,
3 H).
Mixtureof(3S,4aR,10aR)-4a-Ethyl-3,7-dihydroxy-3,4,4a,9,10,10a-
hexahydro-1H-phenanthren-2-one (28) and (2S,4aR,10aR)-4a-
Ethyl-2,7-dihydroxy-1,4,4a,9,10,10a-hexahydro-2H-phenanthren-
3-one (29). A mixture of 27, H2O (25 mL), and acetone was warmed
to 50 °C, and K2CO3 (270 mg, 1.95 mmol) was added. The mixture
was stirred for 1.5 h at 50 °C and then poured into excess aqueous
1 M HCl. The mixture was extracted twice with EtOAc. The
combined extracts were washed with brine, dried (MgSO4), and
concentrated to give a white foam. The mixture (containing some
starting material) was chromatographed using a gradient of 20-40%
EtOAc/hexanes to afford a 2:1 mixture of 28 and 29 (358 mg, 69%).
Compound 28: 1H NMR (CDCl3), selected signals, δ 7.10 (d, J )
8.3 Hz, 1 H), 4.30 (ddd, J ) 1.0, 6.7, 12.7 Hz, 1 H), 3.10 (dd, J )
6.7, 13.0 Hz, 1 H), 2.93-2.90 (m, 2 H), 2.60 (apparent t, J ) 14.5
1
hexanes. H NMR (CDCl3), selected signals: δ 7.18 (d, J ) 8.3
Hz, 1 H), 6.70 (dd, J ) 2.6, 8.3 Hz, 1 H), 6.66 (d, J ) 2.6 Hz, 1
H), 5.22 (br s, 1 H), 4.83 (apparent t, J ) 3.1 Hz, 1 H), 2.94-2.84
(m, 2 H), 2.73-2.61 (m, 3 H), 2.48 (apparent t, J ) 15.6 Hz, 1 H),
2.38 (ddd, J ) 1.8, 4.4, 15.6 Hz, 1 H), 1.99-1.90 (m, 1 H),
1.86-1.78 (m, 1 H), 0.87 (t, J ) 7.8 H, 3 H).
General Procedure for Additions of Lithiopropyne to Ke-
tones 11-15, 28, and 35. (2R,4aR,10aR)-4a-Ethyl-2-prop-1-
ynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol (18). Pro-
pyne gas was bubbled for 6 min into THF (140 mL) at 0 °C. The
solution was cooled to -78 °C, and 2.5 M n-BuLi in hexane (100
mL, 250 mmol) was slowly added to produce a thick white
precipitate. When addition of n-BuLi was complete, the mixture
was stirred in an ice bath for 15 min. A solution of 12 (3.5 g, 14
mmol) in THF (80 mL) was added dropwise. The mixture was
allowed to warm to room temperature overnight and then cooled
1
Hz, 1 H), 2.51 (dd, J ) 4.4, 14.5 Hz, 1 H). Compound 29: H
NMR (CDCl3), selected signals, δ 6.95 (d, J ) 8.3 Hz, 1 H),
4.25-4.21 (m, 1 H), 3.29 (d, J ) 13.0 Hz, 1 H).

Dissociated Glucocorticoid Receptor Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1739
in an ice bath. Aqueous saturated NH4Cl was added to quench the
reaction. The resulting mixture was extracted twice with EtOAc,
and the combined extracts were washed with brine, dried (MgSO4),
and concentrated. The residue was chromatographed, eluting
successively with CH2Cl2 and 5% EtOAc/CH2Cl2. Clean fractions
containing 18 were combined and concentrated to afford a pale-
yellow solid (1.78 g, 45%). A sample for testing and elemental
analysis was obtained by subsequent trituration of some of the
material with CH2Cl2. 1H NMR (DMSO-d6): δ 9.00 (s, 1 H), 6.95
(d, J ) 8.3 Hz, 1 H), 6.48 (dd, J ) 2.1, 8.3 Hz, 1 H), 6.45 (apparent
s, 1H), 5.26 (s, 1 H), 2.77-2.74 (m, 2 H), 2.28-2.25 (m, 1 H),
1.73 (s, 3 H, overlapped), 1.75-1.24 (overlapping m, 9 H),
1.14-1.10 (m, 1 H), 0.62 (t, J ) 7.3 Hz, 3H). LCMS: m/z 267 [M
- OH]+. Anal. (C19H24O2 ·0.5H2O) C, H. The assigned structure
of 18 was confirmed by single crystal X-ray analysis.
was stirred at 0 °C for 1.5 h. The reaction was quenched by addition
of excess aqueous saturated NaHCO3. It was then extracted twice
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and concentrated to provide the corresponding C7
4-nitrobenzoyl ester derivative as a clear oil (223 mg, 100%).
The 4-nitrobenzoyl ester was dissolved in a mixture of MeOH
(8 mL) and CH2Cl2 (4 mL). The resulting solution was cooled to
-78 °C and treated with a stream of O3 for 1 min. The mixture
was purged with a stream of O2. Excess Me2S (1.5 mL) was added.
The resulting mixture was then allowed to warm to room temper-
ature overnight. Evaporation afforded the corresponding C4a
carbaldehyde as a yellow solid.
To cleave the 4-nitrobenzoyl ester, the solid was dissolved in
THF (20 mL) and treated with aqueous 1 M NaOH (10 mL, 10
mmol) for 3 h. Excess aqueous 1 M HCl was added, and the
resulting mixture was extracted with EtOAc. The organic layer was
washed with aqueous saturated NaHCO3, washed with brine, dried
(MgSO4), and concentrated. The corresponding C7 hydroxy-C4a-
carbaldehyde (24 mg, 14%) was isolated by chromatography, eluting
with a gradient of 10-40% EtOAc/hexanes.
The following compounds (2, 17, 19, 20, 30, and 36) were
prepared using the same reaction conditions.
(2R,4aR,10aR)-4a-Methyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene-2,7-diol (17). 17 was prepared from 11.
1H NMR (CDCl3): δ 7.17 (d, J ) 8.3 Hz, 1 H), 6.66 (dd, J ) 3.1,
8.3 Hz, 1 H), 6.58 (d, J ) 3.1 Hz, 1 H), 4.59 (s, 1 H), 2.98-2.82
(m, 2 H), 2.18 (dt, J ) 3.4, 13.0 Hz, 1 H), 2.08 (br s, 1 H),
2.00-1.57 (series of m, 8 H), 1.80 (s, 3 H, overlapped), 1.07 (s, 3
H). LCMS: m/z 253 [M - OH]+. Anal. (C18H22O2) C, H.
The aldehyde was dissolved in MeOH (5 mL), treated with
NaBH4 (20 mg, 0.53 mmol), and stirred for 20 min. The reaction
was quenched by addition of excess AcOH and concentrated. The
residue was taken up in EtOAc, washed with aqueous saturated
NaHCO3, washed with brine, dried (MgSO4), and concentrated.
Compound 21 (a white solid, 5 mg, 3.5% overall) was isolated by
chromatography, eluting with a gradient of 20-50% EtOAc/
(2R,4aS,10aR)-4a-Propenyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene-2,7-diol (19). 19 was prepared from 13.
1H NMR (CDCl3): δ 7.07 (d, J ) 8.7 Hz, 1 H), 6.61 (dd, J ) 2.5,
8.7 Hz, 1 H), 6.53 (d, J ) 2.5 Hz, 1 H), 5.79 (apparent d, J ) 15.5
Hz, 1 H), 4.89-4.79 (m, 1 H), 2.87-2.70 (m, 2 H), 2.31 (dt, J )
3.3, 13.3 Hz, 1 H), 2.00-1.44 (series of m, 8 H), 1.75 (s, 3 H,
overlapped), 1.56 (dd, J ) 1.2, 6.6 Hz, 3 H, overlapped). LCMS:
m/z 279 [M - OH]+. Anal. (C20H24O2 ·0.25H2O) C, H.
1
hexanes. H NMR (CDCl3), selected signals: δ 7.15 (d, J ) 8.3
Hz, 1 H), 6.62 (dd, J ) 2.5 Hz, 1 H), 6.58 (d, J ) 2.5 Hz, 1 H),
3.78 (d, J ) 11.2 Hz, 1 H), 3.64 (d, J 11.2 Hz, 1 H), 2.91-2.80
(m, 2 H), 2.33 (dt, J ) 3.3, 10.0 Hz, 1 H), 2.17-2.07 (m, 1 H),
1.83 (s, 3 H, overlapped).
(2R,4aR,10aR)-4a-Allyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-oc-
(4aS,10aR)-4a-(2-Hydroxyethyl)-2-prop-1-ynyl-1,2,3,4,4a,9,10,
10a-octahydrophenanthrene-2,7-diol (22). A solution of 2 (300
mg, 1.0 mmol) in acetone (40 mL) was cooled to 0 °C in an ice
bath and treated with aqueous 1 M NaOH (1 mL, 1 mmol). The
mixture was stirred in the ice bath for 15 min, 4-nitrobenzoyl
chloride (223 mg, 1.2 mmol) was added, and the resulting mixture
was stirred at 0 °C for 1 h. The reaction was quenched by addition
of excess aqueous saturated NaHCO3 and extracted twice with
EtOAc. The combined organic layers were washed with brine, dried
(MgSO4), and concentrated to provide the corresponding 4-ni-
trobenzoyl ester derivative as a clear oil (447 mg, 100%).
A portion of the 4-nitrophenyl ester (75 mg, 0.17 mmol) was
dissolved in a mixture of MeOH (4 mL) and CH2Cl2 (2 mL). The
solution was cooled to -78 °C and treated with a stream of O3 for
20 s. The mixture was purged with a stream of O2, and excess
Me2S (0.5 mL) was added. The mixture was stirred at -78 °C for
25 min, and then NaBH4 (29 mg, 0.77 mmol) was added. The
cooling bath was removed, and the mixture was allowed to warm
to room temperature. Excess aqueous saturated NH4Cl was added.
The resulting mixture was diluted with H2O and extracted twice
with EtOAc. The combined organic layers were dried (MgSO4) and
concentrated to afford the corresponding 2-hydroxyethyl product
as a clear oil.
To cleave the 4-nitrobenzoyl ester, the oil was dissolved in THF
(10 mL) and treated with aqueous 1 M NaOH (5 mL, 5 mmol) for
3 h. Excess aqueous 1 M HCl was added, and the resulting mixture
was extracted twice with EtOAc. The combined organic layers were
washed with aqueous saturated NaHCO3, washed with brine, dried
(MgSO4), and concentrated. Compound 22 (24 mg, 51%) was
isolated by crystallization of the residue from hot EtOAc/hexanes.
1H NMR (DMSO-d6): δ 9.04 (s, 1 H), 6.95 (d, J ) 8.3 Hz, 1 H),
6.47 (apparent d, J ) 8.3 Hz, 1 H), 6.45 (apparent s, 1 H),
3.40-3.30 (m, 1 H), 3.15-3.07 (m, 1 H), 2.78-2.72 (m, 2 H),
2.25 (apparent d, J ) 13.7 Hz, 1 H), 1.85-1.45 (overlapping m, 7
H), 1.73 (s, 3 H, overlapped), 1.39-1.22 (m, 3 H). LCMS: m/z
299 [M - H]-. Anal. (C19H24O3 ·0.5H2O) C, H.
1
tahydro-phenanthrene-2,7-diol (2). 2 was prepared from 14. H
NMR (CDCl3): δ 7.05 (d, J ) 8.3 Hz, 1 H), 6.63-6.61 (m, 2 H),
5.62-5.53 (m, 1 H), 5.01 (apparent d, J ) 9.8 Hz, 1 H), 4.95
(apparent d, J ) 16.6 Hz, 1 H), 2.99-2.85 (m, 2 H), 2.43 (dd, J )
8.8, 13.5 Hz, 1 H), 2.32 (dt, J ) 3.6, 13.5 Hz, 1 H), 2.10-1.55
(series of m, 9 H), 1.79 (s, 3 H, overlapped). LCMS: m/z 295 [M
- H]-. Anal. (C20H24O2 ·0.2H2O) C, H.
(2R,4aR,10aR)-4a-Propyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydro-phenanthrene-2,7-diol (20). 20 was prepared from 15.
1H NMR (CDCl3): δ 7.06 (d, J ) 7.9 Hz, 1 H), 6.60-6.57 (m, 2
H), 4.55 (br s, 1 H), 2.90-2.82 (m, 2 H), 2.34 (dt, J ) 3.3, 13.3
Hz, 1 H), 1.84 (s, 3 H, overlapped), 1.92-1.49 (overlapping m, 9
H), 1.24-1.10 (m, 2 H), 1.03-0.97 (m, 1 H), 0.77 (t, J ) 7.1 Hz,
3 H). LCMS: m/z 281 [M - OH]+. Anal. Calcd for C20H26O2: C,
80.50; H, 8.78. Found: C, 80.04; H 8.78.
(2R,3S,4aR,10aR)-4a-Ethyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene-2,3,7-triol (30). 30 was prepared from a
3:1 mixture of 28 and 29 (32% from 28). Recrystallized from hot
EtOAc. 1H NMR (CDCl3): δ 7.06 (d, J ) 8.3 Hz, 1 H), 6.63-6.61
(m, 2 H), 3.63-3.58 (m, 1 H), 2.93-2.83 (m, 2 H), 2.59 (dd, J )
4.1, 13 Hz, 1 H), 2.03-1.98 (m, 1 H), 1.94-1.88 (m, 2 H), 1.84
(s, 3 H), 1.82-1.74 (m, 2 H), 1.69-1.63 (m, 2 H), 1.43 (t, J )
12.4 Hz, 1 H), 1.35-1.26 (m, 1 H), 0.78 (t, J ) 7.3 Hz, 3 H).
Anal. (C19H24O3 ·0.25H2O) C, H.
(2S,4R,4aR,10aR)-4a-Ethyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydro-phenanthrene-2,4,7-triol (36). 36 was prepared from
1
35. H NMR (CDCl3): δ 7.06 (d, J ) 8.3 Hz, 1 H), 6.65 (dd, J )
2.6, 8.3 Hz, 1 H), 6.62 (d, J ) 2.6 Hz, 1 H), 4.59 (apparent t, J )
3.1 Hz, 1 H), 2.93-2.80 (m, 2 H), 2.39-2.34 (m, 2 H), 2.09-2.05
(m, 1 H), 1.99-1.92 (m, 2 H), 1.90-1.80 (m, 1 H), 1.86 (s, 3 H,
overlapped), 1.65-1.57 (m, 2 H), 1.50-1.45 (m, 1 H), 0.74 (t, J
) 7.8 Hz, 3 H). Anal. (C19H24O3) C, H.
(4aS,10aR)-4a-Hydroxymethyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene-2,7-diol (21). A solution of 19 (150 mg,
0.5 mmol) in acetone (20 mL) was cooled to 0 °C in an ice bath
and treated with aqueous 1 M NaOH (0.5 mL, 0.5 mmol). The
mixture was stirred in the ice bath for 15 min, 4-nitrobenzoyl
chloride (111 mg, 0.6 mmol) was added, and the resulting mixture
(2R,4aR,10aR)-4a-Ethyl-2-prop-1-ynyl-7-(pyridin-4-ylmethoxy)-
1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-ol (23). To a solution
of 18 (97 mg, 0.34 mmol) in DMF (10 mL) was added 60% NaH

1740 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
in oil (50 mg, 1.3 mmol). The mixture was stirred for 1 h, and
then 4-picolylchloride hydrochloride (67 mg, 0.41 mmol) was
added. After it was stirred overnight, the reaction mixture was
quenched (aqueous saturated NH4Cl), diluted with water, and
extracted twice with Et2O. The combined organic layers were
washed with brine, dried (MgSO4), and concentrated to afford a
yellow oil. During removal of residual DMF under high vacuum,
crystallization of product was evident. The title compound (65 mg,
51%) was triturated with Et2O/hexanes and collected by filtration.
1H NMR (CDCl3): δ 8.69 (d, J ) 5.7 Hz, 2 H), 7.64 (d, J ) 5.7
Hz, 2 H), 7.17 (d, J ) 8.3 Hz, 1 H), 6.76-6.73 (m, 2 H), 5.18 (s,
2 H), 2.97-2.89 (m, 2 H), 2.38 (dt, J ) 3.4, 13.5 Hz, 1 H), 2.10
(br s, 1 H), 1.99-1.91 (m, 2 H), 1.88-1.60 (overlapping m, 6 H),
1.79 (s, 3 H, overlapped), 1.58-1.52 (m, 1 H), 1.29-1.24 (m, 1
H), 0.71 (t, J ) 7.8 Hz, 3 H). LCMS: m/z 376 [MH]+. The
hydrochloride salt was prepared by precipitation from EtOAc with
HCl gas. Anal. Calcd for C25H29NO2 ·HCl·0.5H2O: C, 71.33; N,
7.42; N, 3.33. Found: C, 71.54, H, 6.95; N, 3.06.
drochloride under the same conditions used in the synthesis of 23.
1H NMR (CDCl3): δ 8.48 (d, J ) 4.2 Hz, 1 H), 7.80 (d, J ) 7.8
Hz, 1 H), 7.57 (d, J ) 7.8 Hz, 2 H), 7.34 (apparent t, J ) 7.8 Hz,
2 H), 7.27-7.22 (m, 2 H), 7.06 (d, J ) 8.3 Hz, 1 H), 6.70-6.67
(m, 2 H), 4.98 (s, 2 H), 2.90-2.85 (m, 2 H), 2.63 (s, 3 H),
2.52-2.49 (m, 1 H), 2.42 (dt, J ) 3.6, 13.5 Hz, 1 H), 2.31 (dt, J
) 3.1, 13.5 Hz, 1 H), 2.05-1.86 (overlapping m, 4 H), 1.66-1.60
(m, 2 H), 1.38-1.33 (m, 1 H), 1.27-1.23 (m, 1 H), 0.77 (t, J )
7.3 Hz, 3 H). LCMS: m/z 428 [MH]+. Anal. (C29H33NO2 ·0.5H2O)
C, H, N.
(2R,3S,4aR,10aR)-4a-Ethyl-7-(2-methylpyridin-3-ylmethoxy)-
2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3-
diol (31). 31 was prepared from 30 and 3-chloromethyl-2-
methylpyridine hydrochloride under the same conditions used in
the synthesis of 23. 1H NMR (CDCl3): δ 8.49 (dd, J ) 1.3, 5.2 Hz,
1 H), 7.76 (dd, J ) 1.3, 7.8 Hz, 1 H), 7.19 (dd, J ) 5.2, 7.8 Hz,
1 H), 7.14 (d, J ) 8.3 Hz, 1 H), 6.80-6.76 (m, 2 H), 5.02 (s, 2 H),
3.62 (dd, J ) 3.6, 11.9 Hz, 1 H), 2.98-2.92 (m, 2 H), 2.62 (s, 3
H), 2.62-2.59 (m, 1 H, overlapped), 2.06-1.99 (m, 1 H),
1.96-1.75 (overlapping m, 4 H), 1.83 (s, 3 H, overlapped),
1.72-1.65 (m, 2 H), 1.46 (t, J ) 12.4 Hz, 1 H), 1.35-1.26 (m, 1
H), 0.79 (t, J ) 7.8 Hz, 3 H). LCMS: m/z 406 [MH]+.
(2R,3S,4aR,10aR)-4a-Ethyl-7-(2-methylpyridin-3-ylmethoxy)-2-
phenyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3-diol (33). 33
was prepared from 32 and 3-chloromethyl-2-methylpyridine hy-
drochloride under the same conditions used in the synthesis of 23.
1H NMR (CDCl3): δ 8.47 (d, J ) 3.6 Hz, 1 H), 7.79 (d, J ) 7.3
Hz, 2 H), 7.73 (d, J ) 7.8 Hz, 1 H), 7.34-7.31 (m, 2 H), 7.26-7.24
(m, 1 H, overlapped by CHCl3), 7.19-7.17 (m, 1 H), 7.11 (d, J )
8.3 Hz, 1 H), 6.75 (dd, J ) 2.6, 8.3 Hz, 1 H), 6.70 (d, J ) 2.6 Hz,
1 H), 4.99 (s, 2 H), 4.18 (apparent d, J ) 13.5 Hz, 1 H), 2.89-2.82
(m, 2 H), 2.69 (dd, J ) 4.1, 13.5 Hz, 1 H), 2.24 (dd, J ) 3.1, 14.0
Hz, 1 H), 1.99 (apparent t, J ) 13.0, Hz, 1 H), 1.93-1.88 (m, 1
H), 1.85-1.77 (m, 2 H), 1.74-1.68 (m, 1 H), 1.40-1.36 (m, 1 H),
0.83 (t, J ) 7.8 Hz, 3 H). LCMS: m/z 444 [MH]+. Anal.
(C29H33NO3 ·0.25H2O) C, H, N.
(2R,4aR,10aR)-4a-Ethyl-7-(2-methylpyridin-3-ylmethoxy)-2-
prop-1-ynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-ol (24).
24 was prepared from 18 and 3-chloromethyl-2-methylpyridine
hydrochloride under the same conditions used in the synthesis of
1
23. H NMR (CDCl3): δ 8.50 (d, J ) 5.2 Hz, 1 H), 7.81 (d, J )
7.3 Hz, 1 H), 7.24 (dd, J ) 5.2, 7.3 Hz, 1 H), 7.17 (d, J ) 8.3 Hz,
1 H), 6.79-6.75 (m, 2 H), 5.03 (s, 2 H), 2.98-2.93 (m, 2 H), 2.65
(s, 3 H), 2.39 (dt, J ) 3.4, 13.5 Hz, 1 H), 2.13 (br s, 1 H), 1.99-1.92
(m, 2 H), 1.87-1.63 (overlapping m, 6 H), 1.79 (s, 3 H,
overlapped), 1.61-1.56 (m, 1 H), 1.30-1.26 (m, 1 H), 0.72 (t, J
)
7.3 Hz,
(C26H31NO2 ·0.25H2O) C, H, N.
3
H). LCMS: m/z 390 [MH]+. Anal.
(2R,4aR,10aR)-4a-Ethyl-2-phenyl-1,2,3,4,4a,9,10,10a-octahy-
drophenanthrene-2,7-diol (25). A solution of 12 (200 mg, 0.82
mmol) in THF (6 mL) was cooled to -78 °C and treated with 1.8
M PhLi in cyclohexane (1.8 mL, 3.2 mmol). The reaction mixture
was allowed to warm to room temperature slowly overnight. It was
then quenched by addition of aqueous saturated NH4Cl and
extracted with EtOAc. The extract solution was washed with brine,
dried (Na2SO4), and concentrated to afford an oil containing 25
and its C2 diastereomer. Compound 25 (61 mg, 23%) was isolated
by chromatography, eluting with 18% EtOAc/hexanes. Slow
evaporation from EtOAc/hexanes provided crystalline material. 1H
NMR (CDCl3): δ 7.57 (d, J ) 7.3 Hz, 2 H), 7.34 (apparent t, J )
7.8 Hz, 2 H), 7.28-7.26 (m, 1 H, overlapped by CHCl3), 6.98 (d,
J ) 8.3 Hz, 1 H), 6.56-6.52 (m, 2 H), 4.50 (s, 1 H), 2.86-2.79
(m, 2 H), 2.50 (dq, J ) 3.1, 13.5 Hz, 1 H), 2.40 (dt, J ) 3.6, 14.0
Hz, 1 H), 2.31 (dt, J ) 3.1, 13.5 Hz, 1 H), 2.03-1.84 (series of m,
4 H), 1.80 (br s, 1 H), 1.66-1.56 (m, 2 H), 1.38-1.30 (m, 1 H),
1.25-1.19 (m, 1 H), 0.77 (t, J ) 7.3 Hz, 3 H). LCMS: m/z 305 [M
- OH]+. Anal. (C22H26O2 ·0.25H2O) C, H. The assigned structure
of 25 was confirmed by single crystal X-ray analysis.
(2S,4aS,10aR)-7-(tert-Butyldimethylsilanyloxy)-4a-ethyl-2-
phenyl-1,2,4a,9,10,10a-hexahydrophenanthren-2-ol (37). To a
solution of enone 34 (500 mg, 1.4 mmol) in THF (50 mL) at -78
°C was added dropwise 2 M PhMgBr in THF (2 mL, 4.0 mmol).
The reaction mixture was stirred at -78 °C for 1 h and subsequently
allowed to warm to room temperature over about 1 h. Aqueous
saturated NH4Cl was added to quench the reaction, which was then
diluted with H2O and extracted with Et2O. The organic layer was
washed with brine, dried over MgSO4, and concentrated. The title
compound, an oil (482 mg, 79%), was isolated by chromatography,
1
eluting with 8% EtOAc/hexanes. H NMR (CDCl3): δ 7.51-7.49
(m, 2 H), 7.32-7.23 (m, 4 H), 6.73 (d, J ) 10.4 Hz, 1 H), 6.64
(dd, J ) 2.6, 8.3 Hz, 1 H), 6.57 (d, J ) 2.6 Hz, 1 H), 5.78 (dd, J
) 1.6, 10.4 Hz, 1 H), 2.85-2.75 (m, 2 H), 2.23 (apparent t, J )
13.0 Hz, 1 H), 1.97 (d, J ) 13.5 Hz, 1 H), 1.88-1.82 (m, 2 H),
1.81-1.74 (m, 1 H), 1.61 (br s, 1 H), 1.55-1.48 (m, 2 H), 0.99 (s,
9 H), 0.85 (t, J ) 7.3 Hz, 3 H), 0.21 (s, 6 H).
(2R,3S,4aR,10aR)-4a-Ethyl-2-phenyl-1,2,3,4,4a,9,10,10a-oc-
tahydrophenanthrene-2,3,7-triol (32). 32 was prepared by addition
of PhLi to ketone 28 according to a procedure similar to that used
1
for the preparation of 25. Mp 191-192 °C. H NMR (CDCl3): δ
Hydroboration of Compound 37. A solution of 37 (370 mg,
0.83 mmol) in THF (10 mL) was cooled to 0 °C and treated
dropwise with 1 M BH3 ·THF in THF (8.3 mL, 8.3 mmol). The
mixture was allowed to stir at room temperature overnight. By TLC
analysis, starting material remained. Thus, additional 1 M BH3 ·THF
in THF (5 mL, 5 mmol) was added. After it was stirred for an
additional 2 days, the mixture was cooled in an ice bath. Water
(22 mL), aqueous 10% NaOH (35 mL), and aqueous 30% H2O2
were sequentially added, and the resulting mixture was allowed to
stir at room temperature overnight. Excess peroxide was quenched
by addition of solid sodium thiosulfate. The mixture was neutralized
by sequential addition of AcOH and aqueous 1 N HCl. It was
extracted twice with EtOAc. The combined organic extracts were
washed with water, washed with brine, dried (MgSO4), and
concentrated. The crude product mixture was chromatographed,
eluting with 10% EtOAc/hexanes to afford 38 (oil, 44 mg, 12%),
39 (oil, 45 mg, 12%) as well as the over-reduction products 40
7.78 (d, J ) 7.3 Hz, 2 H), 7.31-7.28 (m, 2 H), 7.24-7.21 (m, 1
H), 7.01 (d, J ) 8.3 Hz, 1 H), 6.57 (dd, J ) 2.6, 8.3 Hz, 1 H), 6.52
(apparent s, 1 H), 4.50 (br s, 1 H), 4.12 (dd, J ) 4.1, 13.0 Hz, 1
H), 2.85-2.75 (m, 2 H), 2.65 (dd, J ) 4.1, 13.0 Hz, 1 H), 2.17
(dd, J ) 2.9, 13.7 Hz, 1 H), 1.96 (apparent t, J ) 13.5, Hz, 1 H),
1.88-1.82 (m, 1 H), 1.80-1.74 (m, 2 H), 1.68-1.63 (m, 1 H),
1.38-1.31 (m, 1 H), 0.80 (t, J ) 7.3 Hz, 3 H). LCMS: m/z 321 [M
- OH]+. Anal. (C22H26O3 ·0.2H2O) C, H. The assigned structure
of 32 was confirmed by single crystal X-ray analysis.
The corresponding 2S epimer (45) exhibited a similar 1H NMR
spectrum to 32 with methine signals at δ 4.24 (dd, J ) 4.1, 11.7
Hz, 1 H) and 2.57 (dd, J ) 4.1, 13.0 Hz, 1 H) in CDCl3. This
spectrum matched exactly that obtained from a sample of the
compound obtained by acid hydrolysis of epoxide 44 (vide infra).
(2R,4aR,10aR)-4a-Ethyl-7-(2-methylpyridin-3-ylmethoxy)-2-
phenyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-ol (26). 26
was prepared from 25 and 3-chloromethyl-2-methylpyridine hy-
1
and 41. The H NMR spectra of 38, 39, and 41 closely resemble

Dissociated Glucocorticoid Receptor Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1741
those reported for 42, 32, and 25, respectively, except for tert-
butyldimethylsilyl (TBDMS) singlets at about δ 1.0 and 0.2.
Hydrolysis of 44 in Aqueous H2SO4/DMSO. To a solution of
44 (76 mg, 0.17 mmol) in water (1 mL) and DMSO (3 mL) were
added 2 drops of concentrated H2SO4. The resulting mixture was
stirred overnight, then heated at 60 °C for a second night. The
mixture was cooled, diluted with water, and filtered to collect a
solid. The solid was dissolved in Et2O, and the resulting solution
was washed with water, dried (MgSO4), and concentrated. The
residue was chromatographed, eluting with 20% EtOAc/hexanes
to afford clean samples of compounds 45 and 46. The 1H NMR of
compound 45 matched exactly that obtained from a sample of the
compound prepared by addition of PhMgBr to ketone 28 (vide
1
Compound 40: H NMR (CDCl3), selected signals, δ 7.44-7.26
(m, 5 H), 7.10 (d, J ) 8.3 Hz, 1 H), 6.63 (dd, J ) 2.6, 8.3 Hz,
1H), 6.60 (d, J ) 2.6 Hz, 1 H), 3.95 (td, J ) 3.6, 10.9, Hz, 1 H),
2.91-2.88 (m, 2 H), 2.83 (dd, J ) 4.2, 12.4 Hz, 1 H), 2.60-2.55
(m, 1 H), 1.00 (s, 9 H), 0.21 (s, 6 H).
(2R,3R,4aR,10aR)-4a-Ethyl-2-phenyl-1,2,3,4,4a,9,10,10a-oc-
tahydrophenanthrene-2,3,7-triol (42). Compound 38 (44 mg,
0.097 mmol) was dissolved in THF (4 mL). Acetic acid (0.12 mL,
2.0 mmol) and 1.0 M tetrabutylammonium fluoride in THF (0.6
mL, 0.6 mmol) were added. The mixture was stirred for 4 h and
then concentrated. The title compound (a white solid, 25 mg, 76%)
was isolated by chromatography, eluting with 15% EtOAc/hexanes.
Mp 207-209 °C. 1H NMR (CDCl3): δ 7.67-7.65 (m, 2 H),
7.38-7.35 (m, 2 H), 7.28-7.26 (m, 1 H), 7.04 (d, J ) 8.3 Hz, 1
H), 6.61-6.57 (m, 2 H), 4.57 (apparent t, J ) 3.1 Hz, 1 H),
2.92-2.82 (overlapping m, 3 H), 2.41 (dt, J ) 2.6, 13.5 Hz, 1 H),
2.33-2.26 (m, 2 H), 2.14-2.08 (m, 1 H), 2.02-1.85 (overlapping
m, 2 H), 1.78-1.73 (m, 1 H), 1.63-1.58 (m, 1 H), 0.79 (t, J ) 7.3
Hz, 3 H). LCMS: m/z 321 [M - OH]+. Anal. (C22H26O3 ·0.33H2O)
C, H. The assigned structure of 42 was confirmed by single crystal
X-ray analysis.
1
supra). Compound 46 H NMR (CDCl3): δ 7.39-7.36 (m, 2 H),
7.31-7.27 (m, 1 H), 7.16 (d, J ) 7.3 Hz, 2 H), 7.00 (d, J ) 8.8
Hz, 1 H), 6.67-6.65 (m, 2 H), 4.69 (br s, 1 H), 3.68 (dd, J ) 7.0,
12.7 Hz, 1 H), 3.28 (d, J ) 13.0 Hz, 1 H), 3.03-2.92 (m, 2 H),
2.46 (d, J ) 13.0 Hz, 1 H), 2.37-2.32 (m, 1 H), 2.25-2.11
(overlapping m, 2 H), 1.93-1.80 (overlapping m, 3 H), 0.82 (t, J
) 7.3 Hz, 3 H). LCMS: m/z 321 [MH]+.
(2S,4bR,8aR)-4b-Ethyl-7-phenyl-4b,5,6,7,8,8a,9,10-octahydro-
phenanthrene-2,6-diol (48). A solution of 44 (100 mg, 0.23 mmol)
in CH2Cl2 (10 mL) was cooled to -78 °C and treated with
BF3 ·OEt2 (0.15 mL, 1.2 mmol). After 10 min at -78 °C, the
reaction was quenched by addition of excess aqueous saturated
NaHCO3 and allowed to warm to room temperature. The mixture
was then diluted with EtOAc. The organic phase was washed with
brine, dried (MgSO4), and concentrated to afford crude 47 as an
oil (91 mg, ∼90%). 1H NMR (CDCl3), selected signals: δ 3.82 (d,
J ) 6.2 Hz, 1 H), 3.03 (d, J ) 13.0 Hz, 1 H), 2.94-2.10 (m, 2 H),
2.45-2.43 (m, 1 H), 2.37 (d, J ) 13.0 Hz, 1 H), 2.30-2.24 (m, 1
H). A portion of crude 47 (50 mg, ∼0.12 mmol) was dissolved in
MeOH (5 mL), cooled to -78 °C, and treated with NaBH4 (20
mg, 0.5 mmol). After being stirred at -78 °C for 10 min, the
mixture was allowed to gradually warm to room temperature over
1.5 h. Aqueous saturated NaHCO3 was added to quench the reaction,
which was then extracted with EtOAc. The extract solution was
washed with brine, dried (MgSO4), and concentrated. The residue
was dissolved in THF (90 mL). Acetic acid (70 µL, 1.2 mmol)
and 1.0 M tetrabutylammonium fluoride in THF (0.25 mL, 0.25
mmol) were added. After 1.5 h, the mixture was concentrated and
chromatographed, eluting with 30% EtOAc/hexanes to afford the
(4bR,8aR)-4b-Ethyl-7-phenyl-4b,5,8,8a,9,10-hexahydrophenan-
thren-2-ol (43). A solution of 12 (500 mg, 2.0 mmol) in THF (20
mL) was cooled to -78 °C and treated with 1 M PhMgBr in THF
(15 mL, 15 mmol). The reaction mixture was allowed to warm to
room temperature over 2 h. It was then quenched by addition of
aqueous saturated NH4Cl and extracted with EtOAc. The extract
solution was washed with brine, dried (MgSO4), and concentrated
to afford an oil containing 25 and its C2 diastereomer. The oil was
dissolved in toluene, treated with KHSO4 (340 mg, 2.5 mmol), and
heated to reflux overnight. The toluene was evaporated, and the
title compound (a white solid, 420 mg, 67%) was isolated by
chromatography, eluting with a gradient of 5-20% EtOAc/hexanes.
1H NMR (CDCl3): δ 7.47 (d, J ) 7.8 Hz, 2 H), 7.34 (apparent t,
J ) 7.3 Hz, 2 H), 7.26-7.23 (m, 1 H), 7.12 (d, J ) 8.3 Hz, 1 H),
6.66 (dd, J ) 2.6, 8.3 Hz, 1 H), 6.59 (d, J ) 2.6 Hz, 1 H),
6.19-6.18 (m, 1 H), 2.94-2.86 (m, 3 H), 2.51-2.48 (m, 1 H),
2.41-2.35 (m, 1 H), 2.16 (apparent d, J ) 18.1 Hz, 1 H), 2.08-2.02
(m, 1 H), 1.96-1.87 (m, 1 H), 1.79-1.74 (m, 1 H), 1.64-1.58
(m, 1 H), 1.48-1.43 (m, 1 H), 1.23 (t, J ) 7.3 Hz, 3 H). Anal.
(C22H24O) C, H.
1
title compound as a white solid (19 mg, 49% from 47). H NMR
(CDCl3): δ 7.42-7.40 (m, 2 H), 7.28-7.18 (overlapping m, 3 H),
7.06 (d, 7.9 Hz, 1 H), 6.61-6.58 (m, 2 H), 4.19-4.15 (m, 1 H),
3.44-3.41 (m, 1 H), 2.88-2.85 (m, 2 H), 2.51 (dd, J ) 4.2, 13.1
Hz, 1 H), 2.12-1.98 (m, 2 H), 1.89-1.56 (overlapping m, 6 H),
1.35-1.25 (m, 1 H), 0.78 (t, J ) 7.5 Hz, 3 H).
Receptor Binding Assays. Compound affinities for human GR
and AR were assessed as previously described.7 Human PR, ERR
and ERꢀ were obtained from PanVera (Invitrogen). The ERR and
ERꢀ binding assays were run in a manner similar to that described
for AR.7 The PR assay was run according to the protocol supplied
by PanVera (Invitrogen).
Whole Cell Functional Assay: IL-1 Stimulated MMP-13
Production. SW1353 human chondrosarcoma cells were plated at
confluence into 96-well plates in Dulbecco’s modified Eagle
medium (DMEM) with 10% fetal bovine serum. After 24 h, medium
was removed and replaced with 200 µL/well serum-free DMEM
containing 1 mg/L insulin, 2 g/L lactalbumin hydrosylate, and 0.5
mg/L ascorbate. The medium was removed 16 h later and replaced
with 150 µL/well fresh serum-free medium containing (20 ng/
mL IL-1ꢀ, (5 nM dexamethasone, (test compound. After 24 h of
incubation at 37 °C and 5% CO2, 125 µL sample from each well
was removed under asceptic conditions for MMP-13 production
analysis (Amersham Bio-Trak MMP-13 ELISA) using the manu-
facturer’s protocol.
Whole Cell Functional Assay: MMTV. Clonal SW1353 human
chondrosarcoma cells stably transfected with pMAM-neo-luciferase
mouse mammary tumor virus (MMTV) reporter construct were
plated near confluence into 96-well plates in DMEM media with
10% fetal bovine serum. After 24 h, medium was removed and
replaced with phenol red-free, serum-free DMEM medium supple-
(6aR,7aS,8aS,9aR)-tert-Butyl-(9a-ethyl-7a-phenyl-5,6,6a,7,7a,8a,
9,9a-octahydro-8-oxacyclopropa[b]phenanthren-3-yloxy)dimethyl-
silane (44). To a solution of 43 (409 mg, 1.3 mmol) and imidazole
(137 mg, 2.0 mmol) in CH2Cl2 was added tert-butyldimethylsilyl
chloride (226 mg, 1.5 mmol). The mixture was stirred overnight.
Analysis by TLC indicated that some starting material remained.
Thus, additional imidazole (44 mg, 0.65 mmol) and tert-butyldim-
ethylsilyl chloride (98 mg, 0.65 mmol) were added. After 5 h of
additional stirring, aqueous 0.5 M citric acid was added. The organic
layer was washed with aqueous saturated NaHCO3, washed with
brine, dried over MgSO4, and concentrated. The residue was
chromatographed, eluting with 50% CH2Cl2/hexanes to afford the
TBDMS ether derivative of 43 (505 mg, 93%). A portion of this
(100 mg, 0.24 mmol) was dissolved in CHCl3 (15 mL), treated
with 57% m-chloroperbenzoic acid (75 mg, 0.25 mmol), and stirred
overnight. The mixture was diluted with CHCl3 and sequentially
washed with aqueous saturated NaHCO3, aqueous NaI, aqueous
Na2CO3, and brine. The resulting solution was dried (MgSO4) and
concentrated. The title compound, an oil (76 mg, 73%), was isolated
1
by chromatography, eluting with 10% CH2Cl2/hexanes. H NMR
(CDCl3): δ 7.46-7.45 (m, 2 H), 7.38 (apparent t, J ) 7.3, 2 H),
7.33-7.30 (m, 1 H), 7.01 (d, J ) 8.8 Hz, 1 H), 6.63 (dd, J ) 2.6,
8.8 Hz, 1 H), 6.56 (d, J ) 2.6 Hz, 1 H), 3.20 (d, J ) 5.7 Hz, 1 H),
2.90-2.75 (m, 3 H), 2.72 (dd, J ) 5.7, 15.0 Hz, 1 H), 2.36 (dd, J
) 11.9, 15.0 Hz, 1 H), 2.16 (dd, J ) 4.4, 14.8 Hz, 1 H), 2.01-1.98
(m, 2 H), 1.90-1.82 (m, 2 H), 1.65-1.61 (m, 3 H), 1.47-1.40
(m, 1 H), 0.99 (s, 9 H), 0.21 (s, 6 H).

1742 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Robinson et al.
D. A.; Humphreys, D.; Inglis, G. G. A.; Johnston, M. J.; Jones, H. T.;
Haase, M. V.; House, D.; Loiseau, R.; Nisbet, L.; Pacquet, F.; Skone,
P. A.; Shanahan, S. E.; Tape, D.; Vinader, V. M.; Washington, M.;
Uings, I.; Upton, R.; McLay, I. M.; Macdonald, S. J. F. Dissociated
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mented with 2 mM L-glutamine, 1 mg/L insulin, 0.5 mg/L ascorbate,
and 2 g/L lactalbumin hydrosylate. Treatments were (dexametha-
sone or compound. After 16 h of incubation at 37 °C and 5% CO2,
100 µL of LucLite reagent (Packard) was added to each well. After
5 min of incubation in the dark, luminescence was detected in a
TopCount microplate scintillation counter.
Computational Details. A homology model of the GR LBD
was built using the Sybyl 6.8 suite of programs (Tripos, Inc., St.
Louis, MO), specifically, the Composer module, used to develop
homology models. The GR model was based on the crystal structure
of the progesterone receptor22 (PDB code 1A28), which had 53.2%
identity to the GR 1D amino acid sequence (Swissprot code
P04150). From the sequence alignment (done using the PAM360
matrix), there was one residue missing from the GR sequence, and
this monomer (SER898) was excised from the PR structure.
Composer was then used to develop a crude homology model,
which was then further optimized with the Sybyl geometry
optimization engine, using Sybyl force field, and a conjugate
gradient decent method, until convergence was reached. The final
rmsd between the PR crystal structure and the GR homology (R
carbons only) model was 0.92 Å. This model was considered
suitable for SAR explorations around GR.
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Acknowledgment. We thank Garth Butterfield, Paul DaSilva-
Jardine, Mark Obukowicz, David Price, Lawrence Reiter, and
Keith Webber for reviewing this manuscript and providing
helpful guidance.
Supporting Information Available: Elemental analytical data
for compounds 2, 3, 5, 7, 8, 10-13, 17-20, 22-26, 30, 32-33,
36, 42, and 43; X-ray crystallographic information and data for
compounds 18, 25, 32, and 42. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) Structure-activity relationships at C7 are, for the most part, outside
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