5(Z)-Benzylidene-1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes as non-steroidal glucocorticoid receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2007.05.062

A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this serie

Full text of DOI:10.1016/j.bmcl.2007.05.062

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4158–4162
5(Z)-Benzylidene-1,2-dihydro-9-hydroxy-10-methoxy-2,2,
4-trimethyl-5H-1-aza-6-oxa-chrysenes as non-steroidal
glucocorticoid receptor modulators
Robert J. Ardecky, Andrew R. Hudson,* Dean P. Phillips, John S. Tyhonas,
Charlotte Deckhut, Thomas L. Lau, Yongkai Li, Esther A. Martinborough,
Steven L. Roach, Robert I. Higuchi, Francisco J. Lopez, Keith B. Marschke,
´
Jeffrey N. Miner, Donald S. Karanewsky, Andres Negro-Vilar and Lin Zhi
Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA
Received 23 March 2007; revised 15 May 2007; accepted 17 May 2007
Available online 23 May 2007
Abstract—A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their
ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure–activity relationships for this
series of compounds are presented.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Prednisolone1 (prednisone) and dexamethasone2 (Fig. 1)
OH
OH
OH
OH
OH
OH
O
H
O
H
O
H
are widely prescribed glucocorticoids for the treatment
of a number of inflammatory conditions. Their use,
however, is restricted because of a range of severe
side-effects including osteoporosis, diabetes, water reten-
tion, and psychosis.3 Both the anti-inflammatory activ-
ity and many of the associated side-effects are
mediated via binding of the glucocorticoid to the gluco-
corticoid receptor (GR). GR, a ligand-regulated tran-
scription factor that binds cortisol, can activate and
repress transcription.4,5 The GR–ligand complex
(GRC) binds directly to glucocorticoid response ele-
ments in the promoter region of regulated genes to acti-
vate gene expression. The GRC can also repress
transcription inhibiting the activity of transcription fac-
tors such as NFjB and AP-1, key regulators of genes
that encode cytokines and other inflammatory media-
tors.5 Mutations to the GR have demonstrated that acti-
vation and repression are distinct functions of the
receptor.6 A glucocorticoid that favors repression over
activation may exhibit less glucocorticoid-related side-
effects while retaining its anti-inflammatory activity.
HO
HO
HO
H
H
H
H
H
F
O
O
O
Prednisolone
Dexamethasone
Cortisol
Figure 1. Steroidal glucocorticoids.
Other side-effects related to the administration of gluco-
corticoids may be attributed to their cross-reactivity
with other nuclear hormone receptors, including the
androgen receptor (AR), progesterone receptor (PR),
and mineralocorticoid receptor (MR).7 Thus identifying
receptor- and gene-selective glucocorticoids with an im-
proved therapeutic index continues to be an active area
of research.8–16
Our SGRM program was based upon the observation
that certain progesterone receptor agonists17 displayed
a significant degree of GR cross-reactivity (Fig. 2). We
have previously disclosed AL-438,9,10 a gene- and recep-
tor-selective glucocorticoid that maintains steroid-like
anti-inflammatory activity but with reduced negative ef-
fects on bone metabolism and glucose control at equiv-
alent anti-inflammatory doses. It was later discovered
Keywords: Glucocorticoid; Hormone receptor; Cortisol; Inflammation;
Prednisolone; Dexamethasone.
*
Corresponding author. Tel.: +1 858 550 4432; fax: +1 858 550
7249; e-mail: ahudson@ligand.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.062

R. J. Ardecky et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4158–4162
4159
affinity for GR. The E-selectin assay was used to evalu-
ate compounds for repression of transcription mediated
by NFjB or AP-1 as an indicator of anti-inflammatory
activity.22
R
5
5
O
R
O
O
5
9
HO9
F
10
O
10
O
N
H
N
H
N
H
The SAR was found to be relatively broad with a num-
ber of substitution patterns well tolerated (Table 1). The
majority of compounds bound with high affinity to GR.
In general, compounds substituted at R1 (5–15) exhib-
ited a partial agonist/antagonist profile in the GRE acti-
vation assay but behaved as efficacious and potent
agonists in the E-selectin repression assay. This type of
profile is distinct from that of classical steroids and sug-
gests that the compounds induce a differential gene reg-
ulation profile compared to ligands with a full agonist
GRE activation profile. This is likely mediated by con-
formational changes in the GRC that result in differen-
tial recruitment of co-activators and co-repressor
proteins through which the GR interacts to regulate
gene transcription.10 We explored a number of analogs
bearing hydrophilic or ionizable groups at R1. Several
of these analogs demonstrated high activity in the E-
selectin repression assay while maintaining a partial
GRE agonist activation profile. Substitution at R2
(16–23) translated to minimal GRE activation agonist
activity while retaining excellent GR-repression activity.
For example, compound 16 had no measurable GRE
activation agonist activity but fully repressed transcrip-
tion in the E-selectin assay. The majority of R3 substi-
tuted analogs (24–31) exhibited an agonist GRE
activation profile and thus had no obvious separation
between activation and repression. Introduction of lar-
ger groups at R3, such as phenyl analog 28, showed re-
duced activity in the E-selectin repression assay.
PR modulators
GR benzylidenes
AL-438
Figure 2.
that incorporation of a 9-OH substituent within this ser-
ies improved compound potency.11 Herein, we describe
the synthesis and characterization of a number of C-5
benzylidene compounds based upon this scaffold that
behave as glucocorticoid receptor modulators (Fig. 2).
We began by systematically exploring structure–activity
relationships (SAR) around the C-5 phenyl group of the
benzylidene motif utilizing readily available benzylic
nucleophiles. We accomplished this by employing two
different synthetic strategies (Scheme 1). Lactone 111
was treated with benzyl Grignard 2, generated from
the corresponding bromide, to yield the intermediate
lactol 4. Alternatively we employed a lateral-lithiation
strategy18 whereby the desired tolyl derivative (with a
neighboring directing group) was treated with a strong
base to give the corresponding lithium anion 3, which
was added to the lactone in a similar manner. This sec-
ond strategy served as a valuable alternative due to dif-
ficulties encountered in the preparation of certain benzyl
Grignard reagents. In both strategies the corresponding
lactol intermediate was subjected to acid-catalyzed
dehydration to give the corresponding C-5 benzylidene
product.19,20
The GR-mediated activity of the compounds was evalu-
ated in a number of biological assays. GR binding was
determined using a radiolabeled dexamethasone com-
petitive binding assay with baculovirus-expressed
GR.11 Direct transcriptional activation by GR was mea-
sured in a cotransfection21 (CTF) assay using an
MMTV:luciferase reporter. This GRE activation assay
can determine agonist or antagonist activity (when com-
pounds are tested in the presence of an EC50 of dexa-
methasone), and provide an estimate of the ligand’s
Activity toward other steroid hormone receptors was
monitored within the series of compounds. The majority
of these compounds were highly GR selective (Table 2).
For example, compound 13 exhibited >1000-fold sepa-
ration in its affinity to GR over other nuclear hormone
receptors.
A number of C-5 heterocyclic analogs were also synthe-
sized. Benzodioxane 33, synthesized via the correspond-
ing benzyl Grignard reagent, appeared efficacious and
potent in E-selectin while retaining an antagonist GRE
activation profile (Table 3). Analogs 34–36 were pre-
pared via a lateral lithiation strategy (Scheme 2). Thie-
nyl and furyl methylidenes 34 and 35 exhibited high
GRE activation agonist activity, whereas pyridyl analog
36 behaved as a partial GRE activation agonist (Table
3). All heterocyclic analogs showed excellent E-selectin
repression activity.
R3
X
R2
R1
R1
OH
R2
O
O
O
R3
HO
HO
2, X = MgBr
3, X = Li
O
O
N
N
H
H
1
R3
4
R2
R1
A number of these compounds were profiled in vivo.
The carrageenan-induced paw edema assay (CPE) is a
classical model of acute inflammation and has been
widely used for profiling anti-inflammatory agents,
including glucocorticoids.23 Rats were dosed orally with
the compound of interest (1, 3, 10, and 30 mg/kg, 5 rats
per dose) and 1 h later carrageenan was injected into the
right hindpaw, causing acute edema. The paw volume
was measured 3 h later. All three representative
TsOH
O
º
CHCl3, 50 C
HO
O
N
H
5-32
Scheme 1. Synthesis of C-5 benzylidene analogs.

4160
R. J. Ardecky et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4158–4162
a
Table 1. In vitro assay results for selected glucocorticoid receptor modulators
R3
R2
R1
O
HO
O
N
H
Compound R1
R2
R3
GR binding
GRE activation
agonist mode
GRE activation
antagonist mode
E-selectin repression
assay
Ki (nM)
EC50 (nM) Eff. (%)
IC50 (nM) Eff. (%)
IC50 (nM) Eff. (%)
Prednisolone
5.3 0.3
0.8 0.3
5.3 3.6
0.6 0.2
130 6.5
19 3.4 1.3 0.5
22 9.1 24 7.6
—
—
4.1 0.8
89 2.0 1.4 0.3
60 3.5 18 2.0
100 1.4
99 1.1
5
6
7
8
F
H
H
H
H
H
H
H
H
Cl
15
18 1.8
3.4 2.9
4.5 1.8
92 3.1
103 1.8
101 1.5
CH3
Ph
1.7 0.5
6.7 1.1
16 1.2 0.4 0.2
13 1.9 3.6 1.5
91 0.5 1.0 0.8
92 1.4 4.4 2.0
O
9
H
F
2.4 0.9
5.1 1.3
56 4.4
11 3.9
56 4.4 3.4 1.5
98 1.0
N
N
10
11
H
H
F
F
3.1
0.9
79 28
19 2.4
58 9.3
85 1.8
—
167 88
—
27
98
O
5.5 0.1
1.9 0.6
95 1.3
N
O O
S
12
H
F
94
108 20
23 1.5 6.6 2.1
73 2.0
22 6.7
93 2.4
N
13
14
15
H
H
H
F
F
F
0.5
1.5
0.6
16 14
356 192
192 111
17 4.9
89 1.4
26 25
70 13
81 4.6
1.0
17
105
59
OH
N
92 4.5 0.1 0.1
44 3.6 0.4 0.1
OH
4.1
107
O
OMe
16
17
18
19
20
21
H
H
H
H
H
H
CH3
CF3
Ph
H
H
H
H
H
H
2.5 0.5
2.7 0.1
7.2 1.5
1.4 0.5
4.1 0.9
4.6
—
—
—
—
—
0.2 0.1
2.5 1.2
2.3 1.3
97 0.4 0.9 0.4
97 0.2 4.1 0.8
104 1.9
94 0.8
102 0.8
101 2.3
94 2.5
62 7.2
—
91 0.1
12 4.4
OH
1.5 0.2
—
32 3.9 4.7 1.3
65 3.4 1.1 0.3
95 0.1 4.7 0.8
OCF3
—
—
1.9 0.2
1.9
OPh
—
94
74 26
S
22
H
H
3.1 0.8
—
—
0.5 0.1
95 0.1 1.4 0.9
101 2.0
23
H
H
1.5 0.1
—
—
0.7 0.1
93 1.9 3.6 0.2
99 1.1
N
24
25
26
27
28
29
30
31
32
H
H
H
H
H
H
H
H
Me
H
Cl
1.7
43 8.5
38 10
207
70 34
39 10
54
—
—
12 5.9
15 2.4
17 8.1
—
95 5.5
91 1.0
94 5.4
—
H
CH3
Et
1.9 0.3
1.9 0.8
2.9 2.3
4.4
12 10
—
55 8.1
—
H
H
i-Pr
Ph
455 69
33
37 8.2
142
—
—
H
—
—
77
88
H
OH
1.1 0.6
1.1 0.8
133 57
437 25
—
15 0.1 0.4 0.1
88 2.3 1.0 0.5
96 0.8
70
H
OCH3 2.7 1.1
133 15
24 3.5
—
—
—
10
H
OCF3
H
4.3 0.4
2.6 0.5
—
—
91
69
CF3
2.6 0.5
96 0.4
15 3.7
95 3.1
a EC50 and IC50 values determined from half-log concentration response curves. Agonist efficacies are represented as the percentage maximal
response in comparison to dexamethasone (100%). Antagonist efficacies are represented as a percent of maximal inhibition of the response of an
EC50 of dexamethasone. E-selectin repression efficacies are represented as a percent of maximal inhibition of the response induced by TNFa and
IL-1b. Standard errors (SEM) represent the mean value of at least three separate experiments with triplicate determinations. If no SEM is noted,
value is from a single determinant. A hyphen (—) denotes an efficacy <10% or potency >1000 nM.

R. J. Ardecky et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4158–4162
Table 2. aBinding cross-reactivity data for selected glucocorticoid
receptor modulators
4161
R
O
i) 37-39, LDA, THF, 0oC
Compound
Binding Ki (nM)
1
HO
ii) TsOH, CHCl3, 50 oC
O
N
GR
PR
AR
MR
N
H
34-36
13
15
16
19
0.5
0.6
970
840
700
630
1100
430
2.5 0.5
1.4 0.5
400 89
750 98
570 130
910 17
ND
290
N
N
S
O
O
O
a Standard errors (SEM) represent the mean value of at least three
separate experiments with triplicate determinations. If no SEM is
noted, value is from a single determinant. ND, no data.
37
39
38
Scheme 2. Synthesis of compounds 34–36.
examples show good to excellent anti-inflammatory
activity in this assay (Fig. 3). Compound 33 was fully
efficacious at 30 mg/kg, compound 34 demonstrated effi-
cacy equivalent to prednisolone at a lower dose of
10 mg/kg.
100
75
50
25
0
Prednisolone
5
33
34
In conclusion, a number of C-5 benzylidene analogs
were prepared and their SAR established. This series
appears to mimic the efficacy of benchmark GCs in
both in vitro and in vivo models of inflammation.
Substitution at the 2- and 3-position of the C-5
benzylidene phenyl ring was well tolerated. A number
of heterocycles were also explored and displayed high
in vitro GR-mediated activity. Representative examples
profiled in vivo demonstrated efficacy equal to that of
prednisolone. The GR-mediated side-effects of com-
pounds within this series will be reported in due
course.
0.1
1
10
100
DOSE (mg/kg)
Figure 3. aIn vivo anti-inflammatory effects of selected compounds.
aCompounds orally administered using an olive oil vehicle.
a
Table 3. In vitro assay results for selected heterocyclic glucocorticoid receptor modulators
R
O
HO
O
N
H
Compound
R
GR binding
GRE activation
agonist mode
GRE activation
antagonist mode
E-selectin repression
assay
Ki (nM)
EC50 (nM)
Eff. (%)
IC50 (nM)
Eff. (%)
IC50 (nM)
Eff. (%)
F
O
33
34
35
36
0.9 0.2
1.4 0.4
3.4 0.6
1.6 0.3
0.2 0.1
0.2 0.1
1.5 0.5
0.7 0.2
18 0.2
0.8 0.2
4.1 1.6
4.9
88 1.6
0.7 0.2
99 5.0
O
N
S
93 6.8
104 23
24 5.2
70 2.8
0.7 0.3
2.4 1.0
4.9 2.5
102 2.1
100 0.8
99 1.7
O
N
O
40
O
N
1.1 0.2
84 3.4
a EC50 and IC50 values determined from half-log concentration response curves. Agonist efficacies are represented as the percentage maximal
response in comparison to dexamethasone (100%). Antagonist efficacies are represented as a percent of maximal inhibition of an EC50 of
dexamethasone. E-selectin repression efficacies are represented as a percent of maximal inhibition of the response induced by TNFa and IL-1b.
Standard errors (SEM) represent the mean value of at least three separate experiments with triplicate determinations. If no SEM is noted, value is
from a single determinant.

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L.; Proudfoot, J.; Nabozny, G.; Thomson, D. S. Bioorg.
Med. Chem. Lett. 2006, 16, 1549.
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not observed.
20. Representative experimental procedure—compound 17.
To a flame-dried 2-neck, 10 ml round-bottomed flask
fitted with a reflux condenser were added magnesium
turnings (28 mg, 2.0 mmol) and diethyl ether (3 ml). A
solution of 3-trifluoromethylbenzyl bromide (478 mg,
2.0 mmol) in diethyl ether was added to the slurry of
magnesium turnings. After 1 h, a solution of 9-hydroxy-
10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno
[3,4-f]quinoline-5-one 1 (30 mg, 0.09 mmol) in diethyl
ether (1 ml) was added. After 18 h, the reaction was
quenched with ammonium chloride (3 ml), extracted with
ethyl acetate (2 · 10 ml), washed with brine (2 · 10 ml),
dried over magnesium sulfate, filtered, and concentrated.
The crude product was purified by precipitation from
dichloromethane/hexanes and collected by filtration. The
product was then dissolved in chloroform and treated with
p-toluenesulfonic acid (1.7 mg, 0.009 mmol) and followed
by TLC (0.1% triethylamine/dichloromethane). After
20 min, the solution was filtered on silica gel, washed with
dichloromethane, and concentrated. The crude product
was then purified by flash chromatography (0.1% trieth-
ylamine/dichloromethane) to afford benzylidene 17 as a
yellow powder (12.8 mg, 30% over 2 steps). 1H NMR
(400 MHz, CDCl3) d 8.18 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H),
7.91–7.84 (m, 1H), 7.48–7.41 (m, 2H), 6.87 (d, J = 10.8 Hz,
1H), 6.85 (d, J = 10.8 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H),
5.65 (s, 1H), 5.56 (s, 1H), 5.53 (s, 1H), 4.21 (br s, 1H), 3.78
(s, 3H), 2.10 (s, 3H) and 1.37 (br s, 6H).
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