Discovery of quinolines as selective glucocorticoid receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2010.07.125

The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respec

Full text of DOI:10.1016/j.bmcl.2010.07.125

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5835–5838
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of quinolines as selective glucocorticoid receptor agonists
a
a
a
a
Stefan Jaroch a, , Markus Berger , Christoph Huwe , Konrad Krolikiewicz , Hartmut Rehwinkel ,
*
Heike Schäcke b, Norbert Schmees a, Werner Skuballa a
a Medicinal Chemistry Berlin, Lead Generation & Optimization, Bayer Schering Pharma AG, Berlin D-13342, Germany
b Common Mechanism Research Berlin, Global Therapeutic Research, Bayer Schering Pharma AG, Berlin D-13342, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 December 2009
Revised 27 July 2010
Accepted 28 July 2010
Available online 3 August 2010
The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other
nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Com-
pounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with
reduced activity in
corticosteroids.
a
transactivation assay, hinting at an improved therapeutic window over
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Glucocorticoid
SEGRA
Transrepression
Transactivation
Quinoline
Since their introduction into the market almost 60 years ago,
glucocorticoids (GCs) maintain a dominant role in the treatment
of inflammatory conditions,1 for example, in the management of
airway diseases,2 rheumatoid arthritis,3 eye and skin diseases (ato-
pic dermatitis, contact eczema, and psoriasis).4 Apart from their
potent anti-inflammatory activity, long-term and high-dose treat-
ment with orally applied GCs can lead to serious adverse effects,
such as osteoporosis, diabetes, Cushing’s syndrome, glaucoma
and muscle atrophy. Recent efforts to elucidate the action of GCs
on a molecular level have led to the hypothesis that the monomeric
GC-bound glucocorticoid receptor abrogates transcription of pro-
inflammatory gene products (transrepression),5 while a dimeric
GC–GR complex promotes inter alia expression of enzymes in-
volved in catabolic processes (transactivation). Hence, interfering
with the transrepression pathway should yield a beneficial anti-
inflammatory effect, whereas triggering the transactivation path-
way rather elicits typical GC side-effects. This rationale opened a
path for improving on a venerable drug class in terms of therapeu-
tic window by decoupling the transrepression from the transacti-
vation activity.6 Though refined and modified in the meantime,7
it served as a valuable paradigm for the identification of novel,
non-steroidal GR agonists, and a host of recent publications attests
to this.6–14 Our early efforts to identify such selective GR agonists
(SEGRAs) led to the discovery of ZK 216348 ((+)-1, Scheme 1).
The compound suppressed the induction of pro-inflammatory
reactions while to a lesser degree affecting enzymes involved in
glucose metabolism, which resulted in an improved systemic
side-effect profile in animal models.15 Since ZK 216348 suffered
from poor selectivity, particularly towards the progesterone recep-
tor (PR), we set out to identify SEGRAs with increased selectivity
for the GR over other nuclear receptors to avoid any adverse effects
mediated by the PR, androgen receptor (AR), or mineralocorticoid
receptor (MR) (cf. Table 1).
Comparison of methylbenzoxazinones 1–4 (cf. Scheme 1 and
Table 1) indicated that the undesired PR activity might be linked
to the heterocyclic moiety. Furthermore, replacing the carboxam-
ide with a methyleneamine functionality, as in 4, appeared to re-
duce binding to AR and MR. In the absence of structural data, we
decided to employ a parallel synthesis approach by opening epox-
ide 14 (cf. Scheme 2) with various amines to identify a suitable sur-
rogate for the methylbenzoxazinone. In addition, we cleaved the
methoxy ether to obtain the hydroxyl analogs, since GR affinity
was observed both for anisole 2 and phenol 3. From these efforts,
naphthalene 6 emerged as a novel lead with a selective binding
profile to GR comparable to that of dexamethasone (DEX), whereas
its methylated congener 5 showed undetectable GR binding affin-
ity. When replacing the naphthalene residue by a quinoline, a sig-
nificant increase in GR binding affinity was recorded for phenol 8,
matching that of methylbenzoxazine 2, but without PR, MR, or AR
binding liabilities. The GR binding affinity of the analogous anisole
7 is reduced, yet comparable to that of 1. In the 2-methylquinoline
series, however, the most potent GR binder is methyl ether 9. In
summary, the quinoline series allows for the reconciliation of
* Corresponding author.
E-mail address: stefan.jaroch@bayerhealthcare.com (S. Jaroch).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.125

5836
S. Jaroch et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5835–5838
OR
F3C
HO
OMe
F3C
HO
F3C
HO
O
H
N
H
N
H
N
N
O
N
O
N
O
O
O
O
O
O
F
F
1
2, R = Me
3, R = H
4
OR
F3C
HO
OR
F3C
H
OR
F
F3C
HO
H
N
H
N
N
N
N
HO
F
F
5, R = Me
6, R = H
7, R = Me
8, R = H
9, R = Me
10, R = H
Scheme 1. Ref. 16.
Table 1
Table 2
Binding profile against nuclear hormone receptorsa
Anti-inflammatory activity in THP-1 monocyte assaysa
Compd
GR
PR
MR
AR
Compd
Transrepression/monocyte inhibition of IL-8 production
pIC50
pIC50
pIC50
pIC50
pIC50
Max. efficacyb (%)
DEXb
1
2
3
4
5
6
7
8
7.9
7.7
9.0
8.5
8.0
<6.0
7.8
7.7
9.0
9.2
8.2
<6.0
7.7
7.9
8.1
7.8
<6.0
<6.0
6.0
<6.0
<6.0
<6.0
<6.0
7.1
8.1
<6.0
6.2
6.3
DEXc
1
3
6
7
8
9
10
8.6
7.5
7.3
<6.0
7.6
7.7
7.6
8.3
100
52
78
71
61
79
90
97
8.9
6.8
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
a
9
10
Ref. 18.
b
Maximal efficacy response is normalized to maximum efficacy of dexametha-
sone (= 100%).
a
Ref. 17.
DEX, dexamethasone.
c
DEX, dexamethasone.
b
OMe
MeO
F3C
MeO
F
F3C
O
F3C
b, c)
a)
d)
CO2Et
HO
+
CO2Et
HO
12
F
F
11
13
14
R
R
MeO
F3C
HO
HO
F
F3C
HO
H
N
H
N
e)
X
X
F
5, X = CH, R = H
7, X = N, R = H
9, X = N, R = Me
6, X = CH, R = H
8, X = N, R = H
10, X = N, R = Me
Scheme 2. Reagents and conditions: (a) AlCl3, 10 °C–rt; (b) LiAlH4, Et2O; (c) PPh3, EtO2CNNCO2Et, THF, 0 °C–rt; (d) ArNH2, DMPU, 130 °C; (e) BBr3, CH2Cl2.
strong GR affinity with selectivity over other nuclear hormone
receptors.
the quinolines 7–10 are potent and efficacious agents: Compound
7 remains comparable to 1, while a higher efficacy renders 8 com-
parable to 3. 2-Methylquinolines 9 and 10 display an efficacy that
almost matches that of DEX.
Next, we evaluated selected compounds in recombinant cell as-
says to assess their anti-inflammatory activity versus side-effect
potential in a similar cellular context. Transrepression (TR) activity,
the main driver for anti-inflammatory activity, was assessed in
HeLa cell lines harboring a collagenase promoter coupled to a
In order to assess how GR binding translates into anti-inflam-
matory efficacy, compounds 6–10, along with dexamethasone
and methylbenzoxazines 1 and 3, were evaluated in LPS-stimu-
lated THP-1 monocytes for their capability to suppress IL-8 pro-
duction (Table 2). Efficacy has been normalized to that of the
dexamethasone reference.18 Despite GR affinity similar to DEX,
naphthalene 6 only poorly suppresses IL-8 formation. In contrast,

S. Jaroch et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5835–5838
5837
Table 3
Anti-inflammatory and immunomodulatory (transrepression) and transactivation activity in recombinant cell assaysa
Compd
Transrepression/transfected HeLa, LUC readout
Transactivation/transfected HeLa, LUC readout
pIC50
Max. efficacyb (%)
pEC50
Max. efficacyb (%)
DEXc
1
3
8
9
8.8
8.2
8.0
8.2
8.7
8.5
100
75
76
84
90
96
8.1
7.9
7.6
7.1
7.6
7.9
100
43
80
50
68
88
10
a
b
c
Ref. 18.
Maximal efficacy response is normalized maximum efficacy of dexamethasone (= 100%).
DEX, dexamethasone.
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luciferase gene. Transactivation (TA) activity, as surrogate marker
for side effects, was determined with MMTV-luciferase transfected
HeLa cells (Table 3).
The TR activity of quinoline 8 is similar to that of meth-
ylbenzoxazines 1 and 3, whereas methylquinolines 9 and 10 ap-
pear to be slightly more potent and efficacious, almost reaching a
DEX profile as in the THP-1 assay. However, this comes at the ex-
pense of increased efficacy and potency in the TA assay in the order
8 < 9 < 10 < DEX. Compound 8 showed the most favorable transac-
tivation profile in the quinoline series, comparable to the bench-
mark ZK 216348 (1) and better than methylbenzoaxine 3. Based
on its GR affinity and selectivity profile, its activity in stimulated
monocytes and its balanced transrepression/transactivation pro-
file, compound 8 demonstrates that the quinoline class of SEGRAs
overcomes drawbacks inherent in the benzoxazine series and has
the potential to improve the dissociation profile.
Compounds 5–10 have been synthesized according to the se-
quence depicted in Scheme 2.19 Friedel–Crafts alkylation of fluoro-
anisole (11) with alkene 12 furnished ester 13.20 Reduction to the
diol and epoxide formation under Mitsunobu conditions gave 14,
which was opened with amines to provide compounds 5, 7, and
9. Finally, methyl ether cleavage led to phenols 6, 8, and 10. This
straightforward process proved particularly versatile at the outset
to identify a methylbenzoxazine surrogate through high-through-
put syntheses with larger amine sets.
In summary, we have discovered quinolines that overcome the
liabilities of our previously reported methylbenzoxazine lead ZK
216348. The prototype 8 displays an improved selectivity profile
versus hormone receptors, an improved in vitro efficacy in mono-
cytes, and a better balance between transrepression and transacti-
vation activities as assessed in recombinant cells. In the course of
our optimization efforts, we eventually identified a development
candidate from this series, the topical SEGRA ZK 245186, which
is currently being evaluated in clinical trials as a novel agent
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Acknowledgments
We thank Stefan Hünicke, Hans-Ulrich Klein, Angela Mücke, Ro-
land Schreyer, Diana Schröder, Harry Vierhufe, and Ricardo Wieseke
for their technical support.
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Anti-inflammatory/immunomodulatory activity in vitro (transrepression):
Inhibition of collagenase promoter activity. HeLa cells stably transfected with
a luciferase reporter gene linked to the collagenase promoter were challenged
with inflammatory stimulus (12-O-tetradecanoylphorbol-13-acetate (TPA)) in
the presence of the reference (dexamethasone) or the test compounds. Tests
were run in duplicate with a pIC50 value error of 0.2.
Transactivation activity in vitro: Induction of MMTV promoter activity has
been used as surrogate marker for transactivation-mediated side effects. The
MMTV promoter was linked to a luciferase reporter gene and HeLa cells were
stably transfected with this construct. Cells were incubated with increasing
concentrations of reference (dexamethasone) or test compounds. Tests were
run in duplicate with a pEC50 value error of 0.2.
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