Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

Article abstract of DOI:10.1016/j.bmcl.2019.126787

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC₅₀ value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.

Full text of DOI:10.1016/j.bmcl.2019.126787

Journal Pre-proofs
Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydro-
genase 1 inhibitors for the potential treatment of ischemic brain injury
Jeong Hyun Lee, Ju Hwan Bok, Sung Bum Park, Haushabhau S. Pagire, Yoon-
Ju Na, Eunyoung Rim, Won Hoon Jung, Jin Sook Song, Nam Sook Kang, Ho
Won Seo, Kwan-Young Jung, Byung Ho Lee, Ki Young Kim, Jin Hee Ahn
PII:
S0960-894X(19)30752-8
DOI:
https://doi.org/10.1016/j.bmcl.2019.126787
BMCL 126787
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 September 2019
15 October 2019
26 October 2019
Please cite this article as: Lee, J.H., Bok, J.H., Park, S.B., Pagire, H.S., Na, Y-J., Rim, E., Jung, W.H., Song, J.S.,
Kang, N.S., Seo, H.W., Jung, K-Y., Lee, B.H., Kim, K.Y., Ahn, J.H., Optimization of cyclic sulfamide derivatives
as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury, Bioorganic
& Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126787
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Optimization of cyclic sulfamide derivatives as 11-
hydroxysteroid dehydrogenase 1 inhibitors for the potential
treatment of ischemic brain injury
Jeong Hyun Leea, Ju Hwan Boka, Sung Bum Parka, Haushabhau S. Pagireb, Yoon-Ju Naa,c,
Eunyoung Rimd, Won Hoon Junga, Jin Sook Songa,Nam Sook Kangc, Ho Won Seoa, Kwan-
Young Junga,d, Byung Ho Leea,c, Ki Young Kima,c,*, Jin Hee Ahnb,*
a Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology,
Daejeon 34114, Republic of Korea
b Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005,
Republic of Korea
c Graduate School of New Drug Discovery and Development, Chungnam National University,
Daejeon 34183, Republic of Korea
d
Department of Medicinal Chemistry and Pharmacology, University of Science and
Technology, Republic of Korea
* Corresponding author:
Ki Young Kim
E-mail: kykim@krict.re.kr
Tel: +82-42-860-7471
Fax: +82-42-861-0770
Address: Therapeutics & Biotechnology Division, Korea Research Institute of Chemical
Technology, P.O. Box 107, Yuseong-gu, Daejeon 34114, Republic of Korea

Jin Hee Ahn
E-mail: jhahn@gist.ac.kr
Tel: +82-62-715-4621
Fax: +82-62-715-2866
Address: Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju
61005, Republic of Korea

Abstract
The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol regenerating enzyme
that amplifies tissue glucocorticoid levels, plays an important role in diabetes, obesity, and
glaucoma and is recognized as a potential therapeutic target for various disease conditions.
Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate
ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to
treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro
activivity with an IC50 value of 1 nM toward human and mouse 11β-HSD1 and showed good
11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in
the transient middle cerebral artery occlusion model in mice, 6e treatment significantly
attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion
injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.
Keywords: 11β-hydroxysteroid dehydrogenase type 1, inhibitors, cerebral ischemia,
neuroprotection, middle cerebral artery occlusion

Stroke is one of the leading causes of mortality and adult disability worldwide, and ischemic
stroke accounts for over 80% of total stroke patients1. Till date thrombolytic therapy is the
most effective treatment in the acute phase of cerebral ischemia, but the intravenous
thrombolysis with tissue plasminogen activator, the only US FDA-approved drug therapy for
ischemic stroke, is limited by its narrow therapeutic window after stroke onset and by the risk
of increasing intracranial bleeding. Thus, there is a definite unmet medical need for the
development of effective and safe therapeutic options such as neuroprotective agents that will
benefit to ischemic stroke patients2.
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that regulates glucocorticoid
levels in tissues by converting inactive cortisone to hormonally active cortisol in humans and
inactive 11-dehydrocorticosterone to active corticosterone in rodents3. 11β-HSD1 is
expressed in the key metabolic tissues including liver, kidney, adipose tissues, skeletal
muscle, and brain4. 11β-HSD1 has been shown to have a putative role in various pathological
conditions such as metabolic syndrome, osteoporosis, and glaucoma4,5. In addition, the results
of the previous studies indicated that 11β-HSD1-mediated abnormal production of circulating
stress hormone glucocorticoid and inflammatory responses during aging, chronic stress or
acute neurological insults are associated with exacerbation of cognitive decline and/or
neuronal cell death6,7. In fact, deficiency or pharmacological inhibition of 11β-HSD1
prevented glucocorticoid-associated chronic stress- or age-related impairment of cognitive
functions8-10. A recent study has also shown pharmacological inhibition of 11-HSD1 exerts
protective effects against oxygen glucose deprivation-induced injury in cortical and
hippocampal neurons as well as transient focal cerebral ischemia in rats11. Therefore,
pharmacological modulation of 11β-HSD1 has become an emerging potential therapeutic
target for the neuroprotective treatments in ischemic stroke.

In our previous study, a series of cyclic sulfamide derivatives was synthesized and evaluated
for their ability to inhibit 11β-HSD112. Among this series, sulfamide derivatives having
adamantyl group showed good in vitro activity as well as in vivo efficacy. In continuation of
our efforts, we have further optimized cyclic sulfamide derivatives, herein we report
synthesis and biological evaluation of cyclic sulfamide derivatives containing adamantyl
group and further explore neuroprotective effects against transient cerebral
ischemia/reperfusion injury.

A series of cyclic sulfamide derivatives was synthesized according to Scheme 1.
Chlorosulfonyl isocyanate (1) reacted with methanol to provide methyl
(chlorosulfonyl)carbamate, which was converted to sulfamide (2a-k) by introduction of
diverse aniline or 2-aminopyridine. Compound 2a-k was cyclized by Mitsunobu reaction to
give 3a-k, followed by hydrolysis to produce 4a-k. Compound 4a-k was coupled with ethyl
bromoacetate and hydrolyzed to give 5a-k, which was amidated by 4-aminoadamantane-1-
carboxamide with EDCI to give the final compound 6a-k.
Scheme 1
Reagents and condition: a) MeOH, CH2Cl2, 0 oC, 15 min; b) R1NH2, triethylamine, CH2Cl2, 0
oC to room temperature, 12 h; c) substituted and unsubstituted propane-1,3-diol, PPh3, DIAD,
o
THF, 0 C to room temperature, 1 - 3 h; d) NaOH, MeOH, H2O, room temperature, 12 h; e)
o
ethyl bromoacetate, NaH, THF, 0 C to room temperature, 3 h; f) LiOH.H2O, THF, H2O,
room temperature, 5 h; g) (E)-4-aminoadamantane-1-carboxylic acid amide hydrochloride,
EDCI, HOBt, DMSO, IPA, room temperature, 5 h.

In previous paper, we identified compound 6a, which showed good in vitro activities with
IC50 values of 1 and 2 nM toward human and mouse 11-HSD1, respectively. During the
previous optimization works12, adamantyl carboxamide moiety was essential for in vivo PK
profile with a good in vitro inhibition activity. Also, methyl substituent on cyclic sulfamide
ring showed good in vitro activities toward human and mouse 11-HSD1, respectively, as
well as liver microsomal stability. Therefore, we further optimized trichlorophenyl moiety
keeping adamantyl carboxamide and methyl substituted cyclic sulfamide moiety.
We further optimized 6a to improve in vivo efficacy for targeting ischemic brain injury. In
vitro inhibition activity of 11-HSD1 was assessed by a HTRF cortisol concentration assay.12
Carbenoxolone was used as a reference. First, an optimization of 6a was proceed by
introducing diverse substituents on trichlorophenyl ring. Aromatic phenyl or furyl
substitutents (6b and 6c) displayed weak inhibitory activities (231 and 49 nM toward human
11-HSD1, respectively. Whereas, methyl substitution (6d) showed better in vitro activity
with an IC50 value of 14 nM for human. Trifluoromethyl and bromo substituted compounds
(6e and 6f) were most active in the series with IC50 values of 1 nM toward human and mouse
11-HSD1. Incorporation of heteroaromatic such as pyridine into the structures (6g and 6h)
also lead reduced in vitro potency.

Table 1. In vitro inhibitory activity of compounds 6a-k against human and mouse 11β-HSD1
Human
Mouse
No
Compound
6a
Structure
11HSD1
11HSD1
IC50 (nM)a
IC50 (nM)b
O
O
Cl
O
1
1
2
N
N
NH2
S
N
N
H
O
Cl
O
Cl
Cl
O
N
NH2
S
N
H
2
3
4
231
174
6b
6c
6d
O
Cl
O
O
Cl
O
N
N
NH2
49
14
68
S
N
H
O
Cl
O
O
O
Cl
O
3.7
N
N
NH2
S
N
H
O
O
Cl
O
Cl
O
N
N
5
6
7
1
1
1
1
6e
6f
NH2
S
N
H
O
Cl
O
F3C
O
Cl
O
N
N
NH2
S
N
H
O
Cl
O
Br
O
O
17
1207
6g
N
N
N
NH2
O
S
N
H
O
O
O
N
N
N
8
9
1.7
1
940
1
6h
6i
NH2
S
N
H
O
O
F3C
O
Cl
O
N
N
NH2
S
N
H
O
O
F3C
Cl
O
Cl
Cl
O
O
10
529
695
6j
N
N
NH2
S
S
N
H
O
Cl
O
F3C
O
11
12
981
2803
6k
N
N
O
NH2
N
H
O
F3C
Cl
Carbenoxolone
1630
243
a
IC50 values were determined from concentration-dependent inhibition curves of triplicate
experiments by GraphPad Prism software.

Compound 6e was further modified on the cyclic sulfamide ring. Removal of a methyl group
on the cyclic sulfamide ring 6i retained in vitro activity with IC50 values of 1 nM toward
human and mouse 11-HSD1. Compound 6j and 6k having ethyl and isopropyl group
showed dramatically loss of inhibitory activities.
Thus, from in vitro results (Table 1), we selected compounds13 6a, 6d, 6e, 6f and 6i for
further evaluation. We performed in vivo 11-HSD1 inhibition study in the brain. After 20 or
30 mg/kg oral dosing, 11-HSD1 inhibition was measured in the brain. Compound 6e
exhibited most promising in vivo 11-HSD1 efficacy. (Table 2)
Table 2. In vivo 11-HSD1 inhibition study in the brain
a
a
b
Human
Mouse
% 11HSD1
No
1
Compound
In vivo dose
30 mg/kg
Inhibition in the
11HSD1
11HSD1
brain
IC50 (nM)
IC50 (nM)
1
14
1
2
3.7
1
66.05 ± 4.27
69.05 ± 11.55
82.03 ± 6.86
41.14 ± 13.28
45.80 ± 5.81
6a
6d
6e
6f
2
20 mg/kg
3
4
5
20 mg/kg
20 mg/kg
20 mg/kg
1
1
1
1
6i
a
IC50 values were determined from concentration-dependent inhibition curves of triplicate
experiments by GraphPad Prism software.
b 11-HSD1 inhibition values in the brain expressed as means ± S.E.M. (n=3-4/group).

To evaluate 11-HSD1 enzyme inhibitory activity of 6e in the brain, ELISA assay for cortisol
quantification was performed in the brain at 1 h after intravenous administration of diluted 6e.
As shown in Figure 1, 6e dose-dependently inhibited 11-HSD1 enzyme activity in the brain.
Especially, administration of 100 mg/kg and 300 mg/kg of 6e showed significant inhibition of
brain 11-HSD1 enzyme activity (*P < 0.05, ***P < 0.001).
Figure 1. Dose-dependent effect of 6e on 11-HSD1 inhibitory activity in the brain of mice.
Diluted 6e compound was administered intravenously to the tail of mice. One hour after
intravenous administration, animals were euthanized by cervical dislocation and brain tissue
was obtained. The brain tissue was placed in a brain slicer mold, and the third section from
the frontal lobe was used in the measurement of 11-HSD1 enzyme inhibitory activity.
Values are expressed as means ± S.E.M. (n=3-4). *P < 0.05, ***P < 0.001 versus vehicle
group.
Since successful application of neurotherapeutics requires effective concentrations in the
brain, poor permeability across the blood-brain barrier (BBB) hinders their therapeutic effects
against cerebral ischemia as well as various central nervous system diseases14. Therefore, we
investigated whether 6e could cross the BBB and achieve efficacious concentrations within

the brain. Accordingly, the concentration of 6e (10 mg/kg) was examined in brain tissue
and plasma at 0.5 and 3 h after intraperitoneal administration to assess drug permeability
across the BBB. The concentration of 6e in plasma was 4.77 ± 0.56 and 1.31 ± 0.36 µg/ml,
whereas, brain levels were 1.78 ± 0.018 and 0.67 ± 0.10 µg/ml at 0.5 and 3 h, respectively
(Fig. 2A). The brain –to-plasma ratio was calculated as 0.38 and 0.53 at each time point (Fig.
2B). Based on Lobell’s report15, 6e was classified as central nervous system active compound.
Our data including brain concentration and brain-to-plasma ratio suggest that sufficient
partitioning across blood-brain barrier in brain disease might support 6e efficacy in mouse
model of ischemic brain injury.
Figure 2. Plasma and brain concentration (A) and brain-to-plasma ratio (B) of 6e following a
single intraperitoneal administration at 10 mg/kg in mice (n=3-4).
To investigate whether 6e have beneficial effects against cerebral ischemia/reperfusion injury,
mice were subjected to 1 h occlusion of middle cerebral artery followed by 24 h reperfusion
(see supporting information). 6e (3, 10 or 30 mg/kg) or vehicle (0.5% carboxymethyl
cellulose) was intraperitoneally administered twice at 1 and 5 h after induction of ischemia,
respectively. At 24 h after reperfusion, neurological deficit score and the infarct size were
measured. Representative images from the TTC-staining (Fig. 3A) and quantitative analysis

showed that 6e at 10 and 30 mg/kg significantly reduces cerebral infarct volume compared to
the vehicle-treated group (66.2 ± 2.7 and 59.0 ± 3.7 vs. 90.3 ± 6.0 mm3, respectively; Fig. 3B)
in a dose dependent manner. Correspondingly, 6e (10 and 30 mg/kg) significantly reduced the
infarct areas compared to the vehicle-treated group (Fig. 3C). Furthermore, 6e at dose of
30ꢀmg/kg significantly improved neurological outcome compared to the vehicle-treated group
(1.1 ± 0.1 vs. 2.1 ± 0.2; P < 0.01) at 24 h after reperfusion (Fig. 3D).
Figure 3. Dose-dependent effect of 6e on the infarct volume and neurological outcome in
mice subjected to 1 h occlusion of middle cerebral artery followed by 24 h reperfusion. Drugs
were given by intraperitoneal injection at 1 and 5 h after induction of ischemia. (A)
Representative images of TTC-stained 2-mm thick coronal brain sections. (B) Quantitative
analysis of the infarct volume and (C) infarct area of mice threated with 6e or vehicle. (D)
Neurological deficit score at 24 h after reperfusion. Values are expressed as means ± S.E.M.
(n=7-9). * P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle-treated group.

We also identified the binding mode for 6e for human and mouse 11-HSD1. The binding
mode for 6e was shown for human and mouse 11-HSD1 in Figure 4. The used reference
structure for 11-HSD1 complex was obtained from the protein data bank (pdb entry; 2ILT16
for human, 1Y5R17 for mouse). The calculation for docking was carried out using LigandFit18
interfaced with Discovery Studio 2018 R2 (BIOVIA, San Diego, CA, USA). 6e interacts
through H-bonding with S170 residue in the active sites in 11-HSD1, and also shows the
hydrophobic interaction with L217, V227 and L230 in human form. In mouse 11-HSD1,
also, H-bonding with S170 residue in the active sites is conserved and showed H-bonding
with N177 and thus was considered to show similar activity.
(A) Structure of 6e
O
Cl
O
N
N
NH2
S
N
H
O
O
F3C
Cl
(B) Binding mode
Human
Mouse

Figure 4. Structure (A) and the binding mode (B) of compound 6e. (B) The binding mode of
6e compound was shown for human (left) and mouse (right) 11-HSD1. The important
residues for the interaction are represented by one-letter codes. The dotted blue lines
represent H-bonding interaction. 6e is shown elemental colors by stick and co-factor,
NADPH is omitted.
In summary, we optimized cyclic sulfamide derivatives containing adamantyl group, and
newly identified 6e, which demonstrated a good in vitro activity with an IC50 value of 1 nM
towards human and mouse 11β-HSD1. Compound 6e showed good 11β-HSD1 inhibition in
ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle
cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume
and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding
modes of 6e for human and mouse 11β-HSD1 were suggested.
Acknowledgments
We would like to acknowledge the financial support from the R&D Convergence Program
(CCP-13-20-KRICT) and the DRC program (DRC-15-01-KRICT) of National Research
Council of Science & Technology, and a project of the Korea Research Institute of Chemical
Technology, the Ministry of Knowledge Economy, Republic of Korea. This work was
supported by the National Research Foundation of Korea (NRF) grant funded by the Korea
government (NRF2018M3A9A7053266, 2018M3A9B5024067)
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