Discovery of the potent non-steroidal glucocorticoid receptor modulator BAY 1003803 as clinical candidate

Article abstract of DOI:10.1016/j.bmcl.2020.127298

We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure, considerations were made as to how physicochemical properties and safety concerns relate to structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with a pharmacokinetic profile suitable for topical application.

Full text of DOI:10.1016/j.bmcl.2020.127298

Journal Pre-proofs
Discovery of the potent non-steroidal glucocorticoid receptor modulator BAY
1003803 as clinical candidate
Markus Berger, Ekkehard May, Hartmut Rehwinkel, Heike Schäcke, Roland
Neuhaus, Antje Rottmann, Thomas M. Zollner, Stefan Jaroch
PII:
S0960-894X(20)30409-1
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127298
BMCL 127298
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
25 March 2020
25 May 2020
29 May 2020
Please cite this article as: Berger, M., May, E., Rehwinkel, H., Schäcke, H., Neuhaus, R., Rottmann, A., Zollner,
T.M., Jaroch, S., Discovery of the potent non-steroidal glucocorticoid receptor modulator BAY 1003803 as
clinical candidate, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
2020.127298
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Discovery of the potent non-steroidal glucocorticoid receptor modulator
BAY 1003803 as clinical candidate
Markus Bergera,*, Ekkehard Mayb, Hartmut Rehwinkela, Heike Schäckec, Roland Neuhausd,
Antje Rottmannd, Thomas M. Zollnerc, Stefan Jaroche
a Medicinal Chemistry Berlin, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany
b Cross Indication Research, Innovation Campus Berlin, Research & Development, Pharmaceuticals, Bayer AG,
D-13353 Berlin, Germany
c Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Research & Development,
Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany
d Drug Metabolism and Pharmacokinetics, Research & Development, Pharmaceuticals, Bayer AG, D-13353
Berlin, Germany, Germany
eOpen Innovation, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany
Abstract:
We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid
receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course
of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure,
considerations were made as to how physicochemical properties and safety concerns relate to
structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired
with a pharmacokinetic profile suitable for topical application.
Keywords:
Glucocorticoid, SEGRA, Transrepression, Transactivation, Amino alcohol
For more than 70 years, glucocorticoids (GCs) have been used to treat severe inflammatory
conditions,1 such as asthma,2 rheumatoid arthritis,3 and eye and skin diseases including atopic
dermatitis, contact eczema, and psoriasis.4 Since long-term, high-dose treatments 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 thus to devise efficacious yet
safer GCs. The concept that beneficial, anti-inflammatory effects are exerted through the
transrepression pathway, while side-effects are triggered through the transactivation activity of
GCs has served as a valuable hypothesis in the quest for novel GCs. Briefly, this concept
maintains that the monomeric GC-bound glucocorticoid receptor abrogates 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 transactivation
1

pathway to a minor extent as partial agonists or even as antagonists.6 This hypothesis is indeed
quite simplistic and, consequently, has been refined to reflect the complexity of GC and
glucocorticoid 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).8,9,10
Based on our discovery of novel selective glucocorticoid receptor agonists (SEGRAs) such as
quinoline 1 (Scheme 1)11 , followed by careful inspection of the its synthetic routes, we
concomitantly discovered the tetrahydronaphthalene representative 2 and super-potent
glucocorticoid agonists like amino alcohol 3 12. Our continued optimization of the novel
chemotype 3 towards the clinical candidate BAY 1003803 for the topical treatment of atopic
dermatitis and psoriasis is outlined in this paper.
F
F
OH
MeO
F
Cl OMe
CF3
MeO
Cl SEt
CF3
F
F
OMe
CF3
OH
OH
F
CF3
H
N
N
OH
OH
HO
NH
NH
NH
HN
N
N
O
O
BAY 1003803
1
2
3
Figure 1. Overview of the structural evolution of selective glucocorticoid receptor agonist lead
structures 1, 2, and 3 towards the clinical candidate BAY 1003803.
To build our understanding of the structure activity relationship (SAR) within the amino alcohol
series, we could identify the 2-chloro3-fluoro-4-methoxyphenyl as the most potent substitution
pattern for the benzyl amine moiety. This finding was accomplished through variation of the
aromatic substitution pattern represented by compounds 3a - h (Scheme 2 and Table 1). A major
influence on potency and the relation of transactivation or transrepression behavior was found
for structural changes in the remainder of the scaffold (4 - 12, Figure 2 and Table 1).
2

R2
F
F
F
F
N
R3
R1
S
MeO
Cl
MeO
Cl
N
MeO
Cl
O
MeO
Cl
S
CF3
CF3
OH
CF3
OH
CF3
OH
CF3
OH
OH
NH
NH
NH
NH
NH
N
F
N
F
N
F
N
F
N
F
6
7
4
Cl
5
3a - 3h
MeO
F
Cl
S
MeO
F
S
MeO
F
Cl
N
Cl
O
MeO
F
Cl OH
CF3
MeO
F
CF3
OH
CF3
OH
CF3
OH
CF3
OH
OH
NH
NH
NH
NH
NH
HN
HN
HN
HN
HN
12
11
9
10
8
O
O
O
O
O
Figure 2. Chemical structures of amino alcohol derivatives.
Although the methyl thioether present in 4 and 9 guarantees for maximal potency, the switch
to the methoxy group is beneficial for two reasons: 1) it slightly reduces the transrepression
(198 pM for 5 compared to 118 pM for 4) and transactivation potency (1.45 nM for 5 compared
to 0.28 nM for 4); and 2) it precludes any redox liabilities associated with the thioether group
being present in a drug candidate for topical application. Introduction of a nitrile (6) or a
dimethyl amino group (7 and 12) leads to a strong potency drop out of the pM-range. The free
hydroxyl group (10) at this position can be considered as equipotent to the alkoxy-derivatives.
The choice of the proper heterocyclic amine substituent was guided by physicochemical
parameters in combination with safety requirements, i.e., potential genotoxicity. The parallel
SAR visible from a quinoline quinolone comparison with respect to potency delivered no
differentiation criterium. Differentiation was possible, however, by considering the logP13
(Table 1) of the most potent derivatives which directly influences the aqueous solubility of the
potential candidate. The switch from methylquinoline (3, 4 or 5) to 7-fluoroquinolone (8, 9 or
BAY 1003803) leads to a logP drop of 0.5 to 0.6 for each pair. With respect to our starting point
3 this translates into a solubility improvement of < 1 mg/ml to 12 mg/ml for BAY 1003803,
which might ease the formulation development significantly14.
3

Table 1. Anti-inflammatory and immunomodulatory transactivation activity in recombinant
cell assaysa.
Transactivation
transfected HeLa,
LUC readout
Transrepression
monocyte inhibition of
IL-8 production
Compound
R1
logPb
max. efficacy
max. efficacy
R2
R3
pEC50
pIC50
[%]c
[%]c
Dexamethasone
8.1
8.0
100
29
8.6
8.2
100
78
2
3
3.10
4.9
4.8
4.2
4.6
4.4
4.4
4.1
5.3
3.4
4.5
3.8
3.4
5.3
4.3
3.9
2.4
3.8
4.4
3.3
Cl
H
F
H
H
F
H
H
F
F
F
OMe
Me
OMe
H
9.2
7.9
8.0
8.0
8.0
8.3
8.2
8.9
7.6
87
66
70
47
72
63
77
66
102
9.8
91
3a
3b
3c
3d
3e
3f
3g
3h
4
8.6
8.2
8.7
8.3
8.3
8.3
8.8
7.7
9.9
9.7
8.9
8.3
8.8
10.0
9.2
9.1
8.1
9.4
87
86
69
78
85
82
82
107
98
97
83
77
93
100
92
99
109
95
H
OMe
OMe
F
F
OMe
OMe
Cl
H
OMe
OH
Cl
9.6
8.8
8.8
7.4
8.5
9.4
9.0
8.8
8.4
9.1
89
80
80
66
92
94
88
91
62
85
5
6
7
8
9
10
11
12
BAY 1003803
15
a Ref.
b For experimental determination of logP see supplementary data
c Maximal efficacy response is normalized maximum efficacy of dexamethasone (= 100%).
Since heterocyclic aniline like bicycles are potentially genotoxic16, one objective of the lead
optimization program was to explore the potential risk of the aniline motif and options for
enhancing safety. Therefore, possible aniline metabolites were tested as 5-amino-quinolones in
the Ames test17 for their genotoxic potential (Table 2). The outcome of this Ames screen with
only one Ames-negative amino quinolone derivative enabled the identification of the 7-fluoro-
quinolone as an obvious heterocycle of choice for a safe clinical candidate.
4

Table 2. Ames screen on amino quinolone derivatives.
F
NH2
F
NH2
NH2
N
NH2
NH2
NH2
Compound
F
HN
HN
HN
O
N
O
N
H
HN
O
O
O
O
Ames
result
positive
positive
positive
negative
positive
positive
Combined evaluation of these properties lead to the identification of BAY 1003803 as the most
suitable clinical candidate. Similar to the amino quinolone fragment of this candidate compound
shown in Table 2, the full parent compound BAY 1003803 also subsequently tested Ames
negative. Furthermore, the candidate compound has partial to full agonistic activity for
transactivation with a slightly reduced efficacy of 85%. Extended in vitro characterization in
relevant anti-inflammatory models was carried out to classify BAY 1003803’s activity with
respect to known highly potent steroidal glucocorticoids, which are able to inhibit the release
of cytokines that are related to dermatological diseases like psoriasis and atopic dermatitis.
BAY 1003803 has been tested in parallel with two reference compounds, the very potent topical
glucocorticoid, Clobetasol, and the weaker topical glucocorticoid, Dexamethasone, in primary
human immune cells. BAY 1003803 is somewhat less potent than Clobetasol, but significantly
more potent than Dexamethasone, with similar efficacy for all three compounds in human
peripheral blood mononuclear cells (PBMCs) stimulated with LPS or PHA (Table 3)18,19
.
Table 3. Inhibition of cytokine release in primary human immune cells reported as IC50[nM] /
Efficacy [%].
BAY 1003803
Clobetasol
Dexamethasone
Inihbition of LPS-induced
TNF-α
0.92 ±0.25 / 98±4
0.75±0.28 / 96±1
0.23±0.03 / 102±5
0.14±0.01 / 98±4
6.4±2.6 / 100
4.3±2.3 / 100
IL-12p40
Inhibition of PHA-induced
IL-2
IFN-γ
IL-4
0.88±0.10 / 95±3
0.7±0.5 / 96±6
0.14±0.03 / 97±4
0.16±0.07 / 101±2
0.07±0.02 / 99±2
4.6±1.5 / 100
3.8±2.3 / 100
2.3±1.1 / 100
0.42±0.14 / 99±1
5

The susceptibility of BAY 1003803 to hepatic metabolism was investigated in vitro using
hepatocytes from different species, including human. BAY 1003803 shows moderate CLb in
rat and dog and high CLb in human hepatocytes. BAY 1003803 exhibits moderate permeation
and no evidence for efflux in the Caco-2 model (Table 4).
Table 4 In vitro metabolic stability and permeability of BAY 1003803
CLb,Hep[a] [L/h/kg] (Fmax [%])[b]
Caco-2 Papp A→B [nm/s][c] (ER)[d]
human
rat
0.72 (83)
dog
19 (0.5)
0.94 (28)
1.3 (38)
[a] Blood clearance (CLb) derived from hepatocytes; [b] Maximal predicted bioavailability after oral
administration; [c] Apparent permeability in Caco-2 cells from apical (A) to basolateral (B) compartment; [d]
efflux-ratio (ER) (Papp B→A divided by Papp A→B).
To substantiate the understanding of the hepatic clearance pathways of BAY 1003803 the main
metabolites were identified in incubations with human, rat and dog hepatocytes. In all species
the O-demethylation to M-1 (compound 10) was identified as major metabolic pathway
(Scheme 2). M-1 has similar pharmacological potency compared to BAY 1003803. Therefore,
its exposure should be taken into consideration for assessment of PK/PD correlation in
preclinical pharmacological models and human in vivo. Furthermore, the product of
demethylation of both methoxy groups (M-4) was found in rat and dog, but not in human
hepatocytes. Subsequent glucuronidation of the demethylated metabolites was observed in the
hepatocytes of humans (M-5) and rats (M-2 and M-3).
F
F
OH
OH
OH
OH
O
Cl
O
Cl
+ Gluc
F
F
F
F
F
NH
F
F
NH
F
Glucuronidation
HN
HN
F
O
O
O
O
F
Cl
M-1
(Compound 10)
M-2
OH
Rat hepatocytes
M-5
Human hepatocytes
F
F
Human, Rat, Dog hepatocytes
Demethylation
NH
F
F
F
OH
OH
OH
Cl
HO
Cl
HO
HN
OH
F
F
F
O
+ Gluc
BAY 1003803
F
F
NH
F
F
NH
F
Glucuronidation
HN
HN
O
O
M-4
M-3
Rat hepatocytes
Rat, Dog hepatocytes
Scheme 1 Major metabolites of BAY 1003803 in different species. M-1 verified by comparison
with authentic compound 10 reference material.
6

In vivo pharmacokinetics (PK) of BAY 1003803 were determined in female rats and dogs
accompanied by a PK study with separately administered metabolite M-1 (compound 10) in
male rats. BAY 1003803 showed a high clearance in rat which cannot be explained solely on
the basis of in vitro clearance in rat hepatocytes indicating involvement of additional,
extrahepatic clearance mechanisms. Clearance of metabolite M-1 in rats was determined even
higher compared to the parent compound. The observed moderate clearance in dogs fits well to
the blood clearance predicted from dog hepatocytes. A high clearance in humans as suggested
by human hepatocytes would be beneficial for a topically administered, locally acting
compound helping to avoid systemic side effects. Therefore, the collected in vivo data gave no
contraindication for advancing BAY 1003803 to further in vivo studies aiming for a topical
application (Table 5).
Table 5. In vivo pharmacokinetic data of BAY 1003803 and metabolite M-1 (compound 10).
BAY 1003803 in
female Wistar rat
BAY 1003803 in
female Beagle dog
Metabolite M-1 in
male Wistar rat
Parameter
Dose i.v. [mg/kg]
CLplasma [L/h/kg]
CLblood [L/h/kg]
Vss [L/kg]
5*
1*
1**
6.8
6.0
18
3.0
3.6
7.0
1.9
1.2
1.2
2.1
1.3
terminal t1/2, i.v. [h]
2.9
Vehicle: *PEG400/saline (60/40, v/v), n=3, **PEG400/saline (70/30, v/v), n=3
To produce larger quantities of BAY 1003803 the previously reported stereoselective synthesis
of 320 had to be adapted to the requirements of the presence of the fluoroquinolone and
replacement of the former thioether with a methyl ether. Its synthesis started with condensation
of aminoquinolone 13 and aldehyde 14 to form imine 15 E-selectively (Scheme 6). Before
addition of the anion of trifluoromethyloxiran21 to imine 15 the NH of the quinolone was
exchanged in situ to the tert-butyl dimethyl silyl group by deprotonation with sodium hydride
followed by addition of TBSCl. The so formed silyl compound 16 was added to the lithiated
(S)-1,1,1-trifluoro-2,3-epoxypropane at -95°C and delivered, compound 17 with a
diastereoselectivity of 4/1 towards the desired (S,S)-isomer after aqueous work up. Epoxide 17
was opened with methanol under basic conditions to yield methoxy ether BAY 1003803.22
7

F
MeO
Cl
N
NH2
Cl
H
F
a)
b)
O
F
+
F
N
H
O
MeO
NH
14
13
15
O
F
F
F
MeO
Cl
N
MeO
Cl
O
MeO
Cl
O
CF3
OH
CF3
F
F
NH
F
NH
c)
d)
N
HN
HN
Si
16
17
BAY 1003803
O
O
O
Scheme 2. Synthesis of BAY 1003803: a) Acetic acid, (t-BuO)4Ti, toluene, 120°C, 92%; b)
NaH, THF, 0°C, TBSCl, c) (S)-1,1,1-trifluoroepoxypropane, n-BuLi, THF, hexane, diethyl
ether, -95°C to -10°C, 62%; d) Cs2CO3, MeOH, 56%.
In summary, we report on the discovery of the selective glucocorticoid receptor agonist BAY
1003803 as a safe development candidate for the topical treatment of psoriasis or severe atopic
dermatitis. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with
a physicochemical and pharmacokinetic profile suitable for topical application.
Declaration of Competing Interests
All authors are or have been employees of Bayer AG. The following authors are shareholders
of Bayer AG: Markus Berger, Stefan Jaroch, Ekkehard May, Hartmut Rehwinkel, and Thomas
M. Zollner.
Acknowledgments
The presented content was generated as part of a collaboration with AstraZeneca. We gratefully
acknowledge the fruitful and productive atmosphere with all AstraZeneca colleagues involved.
The authors thank Allison Ann Berger for proofreading the manuscript, Martina Schäfer and
Siegfried Bäsler for the processing of X-ray structural data, and Hans-Ulrich Klein, Harry
Vierhufe, Roland Schreyer and Rosemarie Schmidt for excellent technical assistance
throughout the whole project.
8

Supplementary data
Experimental procedures and spectroscopic data for BAY 1003803 and compounds 8 to 17.
Supplementary data associated with this article can be found, at
Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☒The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
All authors are or have been employees of Bayer AG. The following authors are shareholders of
Bayer AG: Markus Berger, Stefan Jaroch, Ekkehard May, Hartmut Rehwinkel, and Thomas M.
Zollner.
9

10

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15 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. 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 compound. Inhibition
of IL-8 production: IL-8 synthesis was induced by stimulation of the human promyeloic cell line THP-1 with
lipopolysaccharide (LPS). Cells were treated with LPS in the absence or presence of test compounds or reference
(dexamethasone).
16
Shamovsky, I.; Ripa, L.; Börjesson, L.; Mee, C.; Nordén, B.; Hansen, P.; Hasselgren, C.; O’Donovan, M.;
Sjö, P. J. Am. Chem. Soc. 2011, 133, 40, 16168-16185.
17 (a) OECD Test No. 471: Bacterial Reverse Mutation Test, OECD Guidelines for the Testing of Chemicals,
Section 4, 1997, OECD Publishing, Paris; (b) ICH Harmonized Tripartite Guideline, S2(R1) 2012, “Guidance on
Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use”.
18
Brattsand R, Linden M Aliment Pharmacol Ther. 1996, 10 (Suppl. 2), 81-90.
Barnes P.J. Allergy 2001, 56, 10, 928-936.
19
20 Berger, M.; Dahmen, J.; Rehwinkel, H.; Jaroch, S.; Schäcke, H. WO 2008/006627.
21 Yamauchi, Y.; Katagiri, T.; Uneyama, K. Org.Lett. 2002, 4, 173-176.
22 Berger, M.; Rehwinkel, H.; Zollner, T.; May, E.; Hassfeld, J.; Schäcke, H. WO 2009/065503.
Graphical Abstract:
OH
F
MeO
Cl OMe
CF3
OH
CF3
OH
F HN
HN
F
Clinical
Candidate
BAY 1003803
SEGRA
Lead
N
NH
O
12