Discovery of new selective glucocorticoid receptor agonist leads

Article abstract of DOI:10.1016/j.bmcl.2016.12.047

We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid rec

Full text of DOI:10.1016/j.bmcl.2016.12.047

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of new selective glucocorticoid receptor agonist leads
a
a
b
c
c
Markus Berger a, , Hartmut Rehwinkel , Norbert Schmees , Heike Schäcke , Karl Edman , Lisa Wissler ,
⇑
Andreas Reichel d, Stefan Jaroch e
a Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany
b Gynecological Therapies Berlin, Global Therapeutic Research, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany
c Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden
d Research Pharmacokinetics, Early Development, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany
e Global External Innovation & Alliances, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We report on the discovery of two new lead series for the development of glucocorticoid receptor ago-
nists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated com-
pounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray
structure. Closer inspection into the reaction path and analyses of side products revealed a new amino
alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory
activity in vitro.
Received 12 October 2016
Revised 15 December 2016
Accepted 18 December 2016
Available online xxxx
Keywords:
Glucocorticoid
SEGRA
Ó 2016 Elsevier Ltd. All rights reserved.
Transrepression
Transactivation
Tetrahydronaphthalene
Amino alcohol
For more than 60 years, glucocorticoids (GCs) have been used to
treat severe inflammatory conditions,1 such as asthma,2 rheuma-
toid arthritis,3 eye and skin diseases (atopic dermatitis, contact
eczema, and psoriasis).4 Since long-term and high-dose treatment
with orally applied GCs can cause serious adverse effects, e.g.
osteoporosis, diabetes, Cushing’s syndrome, glaucoma, and muscle
atrophy, the last 2 decades have seen tremendous efforts to better
understand the mode of action of GCs on a molecular level and in
using this knowledge to devise efficacious and safer GCs. The con-
cept that beneficial, anti-inflammatory effects are exerted through
the transrepression pathway, while side-effects are triggered
through the transactivation activity of GCs served as a valuable
hypothesis in the quest for novel GCs. Briefly, this concept main-
tains that the monomeric GC-bound glucocorticoid receptor abro-
gates transcription of pro-inflammatory gene products
(transrepression),5 whereas a dimeric GC-GR complex promotes
inter alia expression of enzymes involved in catabolic processes
(transactivation). This rationale showed a way forward to increase
the therapeutic window of GCs by identifying compounds that act
as full agonists in the transrepression pathway, yet affect the trans-
activation pathway to a minor extent as partial agonists or even as
antagonists.6 This hypothesis is indeed quite simplistic and, conse-
quently, has been refined to reflect the complexity of GC and glu-
cocorticoid receptor (GR) biology.7 Nevertheless, it served as a
valuable paradigm for the identification of novel, non-steroidal
GR agonists, and led to new selective GR (transrepression) agonists
(SEGRAs).8–10
Based on our discovery of novel selective glucocorticoid recep-
tor agonists (SEGRAs) such as quinoline 2 by replacing the benzox-
azinone moiety of the original lead 1 yielded compounds with
considerable selectivity against other nuclear hormone receptors
(Scheme 1).8 In an effort to systematically explore the structure
activity relationship around quinoline 2, particularly with the
aim to identify compounds for oral application, we discovered cyc-
lic analogs, exemplified by tetrahydronaphthalene 3, as potent and
metabolically stable SEGRAs. Through careful inspection of the
synthetic pathways, we concomitantly discovered super-potent
glucocorticoid agonists like amino alcohol 4. Our approach towards
these novel SEGRA chemotypes is outlined in this paper.
Our strategy to render the quinolines of type 2 more stable
entailed inter alia reduction of lipophilicity by replacing the quino-
line with more polar heterocycles as well as modification of the
substitution pattern of the fluorophenol moiety. Along these lines,
when synthesizing isoquinolone
sequence of reductive amination and methyl ether cleavage under
8 from imine 6 through a
⇑
Corresponding author.
E-mail address: markus.berger@bayer.com (M. Berger).
http://dx.doi.org/10.1016/j.bmcl.2016.12.047
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Berger M., et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.12.047

2
M. Berger et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
F
O H
MeO
Cl
SEt
CF
O H
F
3
F C
O
CF
O H
3
F C
3
O H
F
H
N
3
H
N
N
N
O
NH
HO
F
NH
N
HO
O
O
N
N
3
4
1
2
Scheme 1. Overview of the structural evolution of selective glucocorticoid receptor agonist lead structures.
MeO
OH
F
F
CF3
OH
CF3
OH
MeO
F3C
HO
MeO
F3C
HO
NH
d)
e)
a)
b)
F
H
F
N
NH
NH
O
O
O
N
H
O
N
H
9
5
6
10
F3C
HO
NH
HO
F3C
HO
NH
MeO
c)
H
N
H
N
F
F
+
O
O
rac-9
7
8
Scheme 2. (a) 5-Aminoisoquinolone, HOAc, rt, 74.4%; (b) NaBH(OAc)3, HOAc, dichloroethane, rt, 68.4%; (c) BBr3 (1 M in CH2Cl2), rt, 51.2% of 8, 16.5% of 9; (d) TiCl4 (1 M in
CH2Cl2), CH2Cl2, ꢀ20 °C – rt, 63.2%; chiral HPLC separation (Chiralpak AD 20 M, solvents hexane/ethanol/diethylamine); (e) BBr3 (1 M in CH2Cl2), rt, 96.3%.
l
Lewis acidic conditions we also obtained a cyclized congener, the
tetrahydronaphthalene 9, apparently stemming from 6 not com-
pletely consumed in the reduction step (Scheme 2). In a more tar-
geted approach cyclization was effectively catalyzed by titanium
tetrachloride yielding 10 followed by ether cleavage with boron
tribromide to 9. We only isolated the diastereomer in which hydro-
xyl and the substituted amino adopt a cis configuration leaving
both amino and trifluoromethyl groups in equatorial positions.
Although the racemic linear congener 8 binds to GR with higher
affinity, transrepression data both in recombinant and primary
assays indicate that tetrahydronaphthalene 9 displays equal anti-
inflammatory activity after separation of enantiomers (Table 1).
Gratifyingly, clearance by liver microsome proved to be reduced
for the cyclic compound (Table 1) which prompted us to further
explore this template as illustrated with six further analogs entail-
ing modification of the gem-dimethyl part of the tetrahydronaph-
thalene core and introducing isoquinolone surrogates.11
Replacing the isoquinolone with a quinolone and fluoroquina-
zoline moiety led to 11 and 12 respectively (Scheme 3). Along with
isoquinolone 9 all three tetrahydronaphthalenes did not display a
Table 1
Anti-inflammatory and immunomodulatory (transrepression) and transactivation activity in recombinant cell assays12; anti-inflammatory activity in THP-1 monocyte assays13
binding profile against nuclear hormone receptors13; stability in human liver microsomes.
;
Cmpd
Transrepression/
transfected
HeLa, LUC readout
Transactivation/
transfected
HeLa, LUC readout
Transrepression/
monocyte inhibition
of IL-8 production
Binding towards nuclear
hormone receptors
Stability in human
liver microsomes
pIC50
Max. efficacy [%]a
pEC50
Max. efficacy [%]a
pIC50
Max. efficacy [%]a
GR pIC50
PR pIC50
MR pIC50
AR pIC50
% recovery after 300
DEXb
2
8.8
8.3
8.4
8.2
7.8
7.4
8.2
8.3
7.7
8.2
7.7
9.8
100
97
82
84
68
93
88
86
79
78
87
91
8.1
7.9
7.6
7.9
7.6
6.8
7.6
7.9
7.4
8.0
6.8
9.2
100
88
63
81
71
120
73
72
57
29
8.6
8.3
8.4
8.2
7.8
7.4
8.2
8.3
7.7
8.2
7.7
9.8
100
97
82
84
68
93
88
86
79
78
87
91
7.9
8.2
8.6
7.7
7.8
6.9
6.9
7.9
7.8
7.2
7.2
7.5
<6.0
<6.0
6.7
6.1
6.1
<6.0
<6.0
6.1
<6.0
<6.0
6.2
<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
<6.0
6.5
NDc
31
13
8d
9
48
11
12
3
13
14
15
22d
4
6.1
ND
ND
98
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
<6.0
86
ND
ND
ND
ND
115
87
6.1
a
b
c
Maximal efficacy response is normalized maximum efficacy of dexamethasone (= 100%).
DEX: Dexamethasone.
ND: not determined.
d
Data given for the racemate.
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M. Berger et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
O H O H
3
O H
O H
O H
F
F
F
F
F
F
CF
CF
O H
CF
3
O H
3
3
CF
O H
CF
3
O H
3
O H
NH
F
NH
NH
NH
NH
HN
N
N
N
N
HN
O
O
11
12
13
14
15
Scheme 3. Tetrahydronaphthalene synthesized for and investigated in this study.
dissociated profile in the recombinant assays comparable to that
e.g. of linear 8. On the contrary, 12 showed a stronger agonistic
profile in the transactivation assay than dexamethasone. A handle
to increase the dissociation bias towards transrepression came
with substituting the geminal dimethyl group with an (S)-mono-
ethyl group. Now, both the respective fluoroquinazoline 3 and
the methylquinoline 13 showed a better potency and efficacy in
the transrepression vs. the transactivation assays comparable to
the linear benchmark compounds 2 and 8. A simple (S)-methyl
substituent as in 14 reduces potency. The quinolone analog 15,
with vic difluoro pattern at the phenol moiety showed a remark-
able profile as partial agonist in transrepression and partial
antagonist in transactivation and thus is the most dissociated
compound in this series.12,13
To build our understanding of the binding characteristics of
tetrahydronaphthalenes, we determined the X-ray structure of
GR ligand binding domain in complex with compound 15.14 The
structure confirmed that compound 15 makes several key interac-
tions that will drive the functional profile (Fig. 1). The quinolone
moiety occupies the same volume as the A and B rings of classical
steroidal glucocorticoids,15 with the amide making direct interac-
tions to both gatekeeper residues Gln570 and Arg611, thus stabi-
lizing the helix 3–helix 5 interface. The interaction in between
helices 3 and 5 is an important agonist trigger across the steroid
receptor family.16 Looking at the 1,2,3,4-tetrahydronaphthalene,
the 2-hydroxyl makes a direct interaction to the Od of Asn564 on
H3. As Asn564 is central for the stabilization of the loop in between
helices 11 and 12,17 this interaction will likely influence receptor
activation by keeping helix 12 in the active conformation. In addi-
tion, the 5-hydroxyl makes a direct interaction to Gln642 on helix
7. While the androgen receptor also has a glutamine residue in the
corresponding sequence position (Gln783AR), structural differences
between the two receptors place Gln783AR further away from the
ligand.18 As such, Gln642 is unique to GR in this position and has
been shown to be a key component for the evolution of the hor-
mone selectivity profile of the receptor.19 Looking at the overall
compound 15 pose within the ligand binding pocket, it is interest-
ing to note that the tetrahydronaphthalene ring is placed perpen-
dicular to the quinolone. This enables the ligand to access the
junction in between helices 3, 7 and 11 through a novel, more
direct, vector compared to the steroidal 17
a vector. Many of the
most potent GR ligands extend into this sub pocket, and the plas-
ticity in this region has been associated with the ligand entry
trajectory.20
Due to its potency and efficacy in the THP-1 assay, metabolic
stability in human liver microsomes, reduced lipohilicity compared
to 13 and a clean profile in the binding assays towards steroid
receptors, we were initially interested in investigating compound
3 in in vivo studies. The in vivo pharmacokinetic profile in adult,
male rats (Table 2) showed moderate blood clearance and an oral
bioavailability of 59%, thus allowing for oral administration.
We demonstrated in vivo efficacy in two anti-inflammatory rat
models (Table 3). Upon oral treatment, compound 3 significantly
inhibited the inflammation induced either by croton oil in Wistar
rats21 or trimellitic anhydride (TMA) in Brown Norway rats22 tak-
ing reduction of ear edema formation as endpoint. The maximum
effect23 of the tetrahydronaphthalene 3 at 30 mg/kg proved to be
stronger than that of prednisolone along with a markedly lower
ED50
.
Hence, we devised a robust and stereoselective synthesis pro-
viding sufficient amounts of material for broad biological profiling
(Scheme 4). The synthesis started with coupling boronic acid 16 to
2-bromo-1-butene followed by a stereoselective ene-reaction with
ethyl trifluromethylpyruvate employing a chiral Lewis acid cata-
lyst.24 As we could not reduce the enantiomerically enriched (R)-
hydroxyl ester 18 with diisobutylaluminum hydride, we took
recourse to lithium aluminum hydride and were delighted to
obtain the aldehyde as main product. We assume that this untyp-
ical outcome is influenced by the a-2-trifluoromethyl substituent.
Hydrogenation of the E/Z double bond over palladium delivered
the aldehyde 19 as a 1:1.2 mixture with its epimer. Separation of
the aldehyde diastereomers was followed by imine formation
(20) and cyclization under Lewis acid catalysis. With the Et, CF3,
and NHHet group occupying an equatorial position, the reaction
is considered to be driven thermodynamically.
For a more detailed exploration of the reaction mechanism
leading to tetrahydronaphthalenes, we examined the cyclization
of imine 21 which harbors a bulky bromo-substituent expected
to hinder cyclization due to steric encumbrance (Scheme 5). Upon
treatment of imine 21 with Lewis acid we obtained a rearrange-
ment product, amino alcohol 22, in addition to the tetrahydron-
aphthalene 23.
Fig. 1. Refined 2mFo-DFc electron density of GR ligand binding domain in complex
with compound 16. The dotted lines represent putative hydrogen bonds.
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4
M. Berger et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Table 2
Physicochemical and pharmacokinetic properties (rat) of compound 3.
Cmpd
Sola [mg/L]
26
logP
4
CLb [L/h/kg]
1.6
Vss [L/kg]
11
t1/2 [h]
5.8
F [%]
59
3
CLb, Vss and t1/2 determined after 1.25 mg/kg bolus i.v.; F determined after 10 mg/kg in microcrystalline suspension.
a
thermodynamic solubility in 0.1 M phosphate buffer pH 7.4 at 25 °C.
Table 3
ED50 values and maximum effects of compound 3 and the reference prednisolone given as mean values standard deviations of n experiments. For calculation of mean ED50
values and maximum effects, inhibition of edema as the major parameter of anti-inflammatory activity has been used.
Cmpd
ED50 [mg/kg]
Max. effect @ 30 mg/kg [%]
3
Prednisolone
3
Prednisolone
Croton oil (n = 3)
TMA (n = 2)
1.4 0.9
1.3 0.0
15.7 2.4
6.7 5.8
124 13
55 10
83 11
107
8
O
MeO
F C
3
O
c
B(OH)
F
b
F
O
a
2
F
HO
18
O
17
16
O H
F
N
CF
O H
MeO
F C
3
MeO
F C
3
3
e
d
N
F
O
F
N
HO
HO
19
F
NH
N
H
F
20
N
3
Scheme 4. (a) 2-Bromo-1-butene, 1 mol% Pd(PPh3)4, toluene, 1-propanol, 120 °C, 5 h, 50%; (b) trifluoropyruvate, 5 mol% Cu[(4S,4S)-bis-(4-phenyl-2-oxazolin-2-yl)propane
(H2O)2]((SbF6)2, CH2Cl2, 93%, E/Z ratio 2:1, E: 9% ee, Z: 58% ee; (c) 1. LiAlH4, diethyl ether, ꢀ15 °C, 73%; 2. H2, Pd/C, methanol, acetic acid, 76%, RR/SR ratio 1:1.2; (d) 7-fluoro-2-
methylquinazolin-5-amine, Ti(OtBu)4, toluene, quant. (e) BBr3, CH2Cl2, ꢀ40 °C to 0 °C, 40%; chiral HPLC separation (Chiracel OD-H 5
l).
2 +
2 +
&)
2 +
ꢀ
&)
2 +
ꢀ
0H2
) &
1+
ꢀ
%U
%U +1
1
1+
a)
2
+
+2
%U
1
+
2
2
1
+
21
rac-23
rac-22
Scheme 5. (a) BBr3 (1 M in CH2Cl2), rt, 50%, 22/23 ratio 1.8:1.
It is tempting to speculate about the reaction mechanism lead-
ing either to a rearrangement or cyclization. We assume one cen-
tral five-membered transition state that either rearranges into
the tetrahydronaphthalene (Scheme 6, path A) or reacts to a termi-
nal alkene under re-establishment of the aromatic ring as a driving
force (path B). Clearly, this reaction deserves more scrutiny to ver-
ify this hypothesis.
(Table 1). Its synthesis started with condensation of aminoquino-
line 24 with aldehyde 25. Addition of the anion of trifluoromethy-
loxiran26 to imine 26 yielded epoxide 27, which was opened with
thioethanol to yield thioether 4. This compound served as a lead
compound for the identification of highly potent GR agonists27
for the topical treatment of atopic dermatitis, which will be
reported in the future as a separate communication.
We would have discarded the rearranged side-product, but
were surprised to observe significant activity in the transrepres-
sion assay (cf. 22 in Table 1).25 Based on this chemotype we
devised analogs that were accessible through a very straightfor-
ward synthesis allowing variations in the aryl ring substitution
pattern, while allowing the exploration of the hydrophobic pocket
occupied by the isopropene moiety (Scheme 7). Thus, we arrived at
thioether 4, which was found to be a picomolar active GR agonist in
the transrepression assay, but displayed reduced dissociation
In summary, we reported on the discovery of two new lead ser-
ies for the development of glucocorticoid receptor agonists. Firstly,
the discovery of tetrahydronaphthalenes led to metabolically
stable and dissociated compounds, particularly 3, which eventually
demonstrated in vivo efficacy and dissociation in animal models
upon oral exposure. Careful investigation of reaction mechanisms
and product mixtures revealed the amino alcohol series providing
pM active agonists, such as 4, that were further developed into
candidates for topical treatment of severe atopic dermatitis.
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M. Berger et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
5
OH
OH
+
O
CF3
OH
NH
CF3
OH
CF3
OH
H
H
R
A
B
R
Br HN
Br
NH
Br
R
H
O
CF3
O
BBr2
+
N
R
Br
H
R
OH
O
CF3
OH
CF3
OH
Br
HN
R
R:
HN
Br
O
N
H
Scheme 6. Potential mechanisms delivering either amino alcohols or tetrahydronaphthalenes.
F
F
F
MeO
MeO
Cl SEt
CF3
Cl
MeO
Cl
N
O
CF3
Cl
H
NH2
O H
a)
c)
b)
F
NH
NH
+
O
MeO
N
N
N
N
27
4
24
25
26
Scheme 7. (a) Acetic acid, toluene, 4 Å molecular sieves 120 °C, 92%; (b) (S)1,1,1-trifluoroepoxypropane, n-BuLi, THF, hexane, diethyl ether, ꢀ95 °C to ꢀ10 °C, 79%, SS/RS ratio
8:1; (c) Cs2CO3, CH3CH2SH, DMF, 44%.
(b) Harcken C, Riether D, Kuzmich D, et al. Med Chem. 2014;57:1583–1598;
A. Supplementary material
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2009;52:1731–1743;
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Med Chem.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.12.
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