Discovery of cyclicsulfonamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.12.035

A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11β-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11β-HSD2.

Full text of DOI:10.1016/j.bmcl.2009.12.035

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1065–1069
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of cyclicsulfonamide derivatives as 11b-hydroxysteroid
dehydrogenase 1 inhibitors
Se Hoan Kim a, Ravirala Ramu b, Sung Wook Kwon a, Su-Hee Lee b, Chi Hyun Kim b, Seung Kyu Kang b,
Sang Dal Rhee b, Myung Ae Bae b, Sung Hoon Ahn b, Duck Chan Ha a, Hyae Gyeong Cheon b,
b,
Ki Young Kim b, , Jin Hee Ahn
*
*
a Department of Chemistry, Korea University, Seoul 121-742, Republic of Korea
b Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit
11b-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar
inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selec-
tivity toward human 11b-HSD2.
Received 13 October 2009
Revised 20 November 2009
Accepted 7 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
11b-Hydroxysteroid dehydrogenase 1
Cyclic sulfonamide
Diabetes
Inhibitor
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an
endoplasmic reticulum-associated enzyme that acts as NADPH-
dependent reductase and converts inactive cortisone to the active
glucocorticoid cortisol (Fig. 1).1
The connection between 11b-HSD1 and type 2 diabetes has
been demonstrated in mouse genetic models. Mice overexpressing
11b-HSD1 in adipose showed metabolic syndrome-like pheno-
types such as central obesity, glucose intolerance, and insulin resis-
tance.2,3 In contrast, 11b-HSD1 deficient mice were resistant to the
development of high-fat diet-induced obesity and exhibited im-
proved insulin sensitivity and lipid profiles.4,5 These data suggest
that 11b-HSD1 could be a drug target for the treatment of meta-
bolic syndrome as well as type 2 diabetes.
During the last few years, small molecule inhibitors for
11b-HSD1 have been reported,6–11 and Incyte and Amgen’s com-
pounds are in clinical trials. Although a number of small molecule
inhibitors were introduced, the discovery of a new scaffold is still
very important. Therefore, the search for new 11b-HSD1 inhibitor
through high throughput screening (HTS) using the chemical
library of Korea Chemical Bank was performed and compound
1a12 was discovered as a hit (Fig. 2).
series of cyclic sulfonamide derivatives was synthesized according
to Schemes 1–3. Saccharin sodium salt 2 was reacted with -bro-
mo ketone or ester in DMF to provide the alkylated product 3. It
is on reaction with sodium in ethanol resulted ring expansion to
provide compound 1 (including hit 1a, R1 = phenyl) and its deriva-
tives, which were further derivatized with diverse alkyl halides
a
and
a-halo ketones to result in the coupled product 4 (Scheme 1).
OH
OH
OH
O
O
O
OH
HO
11β HSD1
H
H
H
H
H
H
O
O
cortisone
cortisol
Figure 1. The role of 11b-HSD1 between cortisone and cortisol.
OH
O
We now wish to report the synthesis of cyclic sulfonamide
derivatives and their biological study for 11b-HSD1 inhibitors. A
NH
S
O
O
1a
* Corresponding authors. Tel.: +82 42 860 7076 (J.H.A.).
E-mail address: jhahn@krict.re.kr (J.H. Ahn).
Figure 2. Chemical structure of compound 1a.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.035

1066
S. H. Kim et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1065–1069
O
OBn O
O
OH
O
O
a
N- Na+
OH
R1
N
a, b
R1
N
S
S
S
N
S
R2
O
O
b
O
O
O
O
O
O
O
2
3
8
4 (R1= OEt, R2= CH2COPh)
d
c, d
OH
O
OH
O
R1
c
R1
OH
O
OH O
R3
NH
N
R2
OH
N
H
S
O
S
O
O
O
N
N
S
S
O
O
4
1
O
O
O
O
Scheme 1. Reagents and conditions: (a) BrCH2COR1 (R1 = methyl, phenyl, OEt),
DMF, 100 °C, 4 h (78–88%); (b) Na, EtOH, reflux, 4 h (53–60%); (c) 1 M NaOH, X-R2
(R2 = methyl, benzyl, phenethyl, CH2COAr), room temperature, 12 h (47–60%).
9
10
Scheme 3. Reagents and conditions: (a) benzyl bromide, K2CO3, toluene, 100 °C,
12 h (80%); (b) LiOH, THF/EtOH/H2O, room temperature, 6 h (90%); (c) aniline or
benzyl amine, EDCI, DMAP, CH2Cl2, room temperature, 12 h (41–53%); (d) 15% aq
HCl/dioxane, reflux, 3–6 h (60–85%).
O
Table 1
O
S
O
In vitro 11b-HSD1 inhibitory activity of cyclic sulfonamide derivatives
OH
O
a
R1
Compound
Structure
IC50
(lM)
a
N
N
OH
O
S
R2
O
O
O
O
1a
14.8
5
4
NH
S
O
O
O
OH
O
b
O
4a
0.388
0.547
O
N
S
O
OTf
O
O
R1
R1
c
O
N
N
R2
S
O
R2
S
O
O
O
O
O
5
6
7
N
Scheme 2. Reagents and conditions: (a) bromoacetophenone, K2CO3, acetone, room
temperature, 3 h (71%); (b) trifluoromethanesulfonic anhydride, pyridine, CH2Cl2,
room temperature, 2 h (90%); (c) 3,4-methylenedioxyphenyl boronic acid, K2CO3,
Pd(PPh3)4, toluene/DMF, reflux, 2 h (75%).
S
O
O
O
O
As shown in Scheme 2, compound 4 was further derivatized
O
7
Not active 35% at 10
l
l
M
M
with
a-bromoacetophenone to give the O-alkylated compound 5.
Also, compound 4 was converted to triflate 6, followed by Suzuki
reaction with a boronic acid derivative to give 7.
N
S
Compound 4 (R1 = OEt, R2 = CH2COPh) was converted to carbox-
ylic acid or amide derivatives (Scheme 3). Benzylation of com-
pound 4 followed by treatment with lithium hydroxide afforded
the corresponding acid 8. The compound 8 was directly converted
to the carboxylic acid 10 under acidic debenzylation condition or
amidated with aniline or benzyl amine to give amide derivatives,
followed by debenzylation under acidic condition afforded the cor-
responding amide 9.
O
O
O
OH
O
O
1b
Not active 23% at 10
NH
S
O
OH
O
O
4b
4.5
0.5
In vitro inhibition activity of 11b-HSD1 was assessed by a HTRF
cortisol assay. Human microsomes were incubated with cortisone,
NADPH, and chemical compound. The IC50 values of compounds
were determined from concentration-dependent inhibition curves.
Carbenoxolone was used as a reference compound.13
N
S
O
O
Carbenoxolone
a
IC50 values were determined by GraphPad Prism software.

S. H. Kim et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1065–1069
1067
Table 3
A high throughput screen was conducted to discover new 11b-
HSD1 inhibitors. Cyclic sulfonamide 1a was identified as a hit with
an IC50 value of 14.8 M. First, the substituent effects of cyclic sul-
fonamide at the 2-, 3-, and 4-position were evaluated as shown in
Table 1. N-Methylated cyclic sulfonamide (4a, IC50 = 0.388 M)
In vitro 11b-HSD1 inhibitory activity of cyclic sulfonamide derivatives
a
l
Compound
Structure
IC50
(lM)
OH
O
l
was shown to have a nearly 50-fold greater potency than that of
the hit compound 1a. However, further O-alkylated compound 5
and 3,4-methyldioxyphenyl substituent at the 4-position 7 exhib-
ited decrease of in vitro activities. Also, substitution of benzoyl
moiety to ester (ethyl ester) at the 3-position 1b and 4b led to de-
crease in vitro potency.
N
4e
0.031
S
O
O
O
OH
O
Next, the substituent effect at the 2-position was further evalu-
ated as shown in Table 2. The methyl analogue 4a showed an IC50
value of 388 nM. Benzyl and phenethyl derivative (4c and 4d) had
an approximately twofold greater potency than the methyl substi-
tuent (254 and 234 nM, respectively). Furthermore, compound 4e
having phenylacetyl group at the 2-position exhibited a good
in vitro potency with an IC50 value of 31 nM. The phenylacetyl
group at the 2-position was fixed, and other substituent effects
were studied and the results were summarized (Table 3). Substitu-
tion of the benzoyl group to the acetyl group (4f) at the 3-position
resulted in a loss of activity. Also the masking of OH at the 4-posi-
tion showed a decrease of in vitro potency (6). An introduction of
acid derivative at the 3-position was found to be detrimental
(4g–4j). Compound 4e was still the most potent, therefore a further
modification at the 2-position was performed.
N
O
4f
Not active 18% at 10
lM
S
O
S
O
F
F
F
O
O
O
O
6
0.74
N
O
S
O
O
OH
O
The substituent effect on the phenyl group at the 2-position,
mouse 11b-HSD1 inhibition potency, selectivity, metabolic stabil-
ity, and PK study were investigated (Table 4). Compound 4e and
other phenyl derivatives (4k–4n) except acid substituent (4o)
showed good in vitro activities toward human 11b-HSD1 with
IC50 values in the range of 28–40 nM. On the other hand, toward
O
N
4g
3.0
S
O
O
O
OH
O
Table 2
In vitro 11b-HSD1 inhibitory activity of cyclic sulfonamide derivatives
OH
a
Compound
Structure
IC50
(
lM)
N
4h
Not active 24% at 10
lM
lM
lM
S
OH
O
O
O
O
4a
0.388
0.254
N
OH
O
S
O
O
O
N
H
OH
O
N
4i
Not active 21% at 10
S
O
O
O
N
4c
S
O
OH
O
N
H
N
OH
O
4j
Not active 38% at 10
S
O
O
O
N
4d
0.234
S
O
Carbenoxolone
0.5
O
a
IC50 values were determined by GraphPad Prism software.
OH
O
mouse 11b-HSD1, compound 4e was the most potent with a mod-
erate inhibitory activity (7.8 M).
l
N
4e
0.031
0.5
S
11b-HSD2 oxidizes cortisol to cortisone utilizing NAD as a co-
factor and is primarily expressed in the kidney, colon, and other
tissues.14,15 Inhibition of 11b-HSD2 might lead to sodium reten-
tion, hypokalemia, and hypertension,14 indicating that inhibitors
for 11b-HSD1 must be selective over 11b-HSD2. Compound 4e
showed a good selectivity against human 11b-HSD2 enzyme. Also,
O
O
O
Carbenoxolone
a
IC50 values were determined by GraphPad Prism software.

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S. H. Kim et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1065–1069
Table 4
In vitro inhibition, metabolic stability, hERG and PK study of cyclic sulfonamide derivatives
a
a
a
Compound
Structure
hHSD1 IC50
M)
mHSD1 IC50
M)
hHSD2 IC50
M)
Microsomal stability
(t1/2
hERG
>100
PK
(l
(l
(l
)
OH
S
O
PO Cmax = 1.1
lg/mL
N
t1/2 = 5.5 h
Cl (L/h/
Kg) = 0.4
F = 48.7%
4e
0.031
7.8
6% at 20
l
M
Human 74.88 min
lM
O
O
O
OH
O
N
S
NTb
NT
NT
O
4k
0.028
36% at 10
lM
O
O
OH
O
N
S
4l
0.030
38% at 10
lM
NT
NT
NT
O
O
O
O
+
N
O
OH
O
N
O
S
4m
0.031
43% at 10
lM
NT
NT
NT
O
O
O
O
OH
O
N
O
S
4n
0.040
9.0
NT
NT
NT
O
O
N
OH
O
N
O
S
4o
0.72
0.5
9.7% at 10
lM
NT
NT
NT
O
O
OH
O
Carbenoxolone
a
IC50 values were determined by GraphPad Prism software.
Not tested.
b
4e was moderately stable in human liver microsomes and exhib-
ited no binding with hERG (>100 M). The rat PK profiles of com-
pound 4e showed moderately good systemic exposure and oral
pound 4e showed good in vitro activity and selectivity. Further
investigation for increasing both human and mouse 11b-HSD1
inhibition activity is in progress.
l
bioavailability with an acceptable clearance and half-life.
In conclusion, we have identified a series of cyclic sulfonamide
derivatives as 11b-HSD1 inhibitors through the screening of a
small-molecule library. Our initial hit compound 1a showed weak
inhibitory activity. Significant improvements in potency were
achieved by modification at the 2-position. The most potent com-
Acknowledgments
This research was supported by the Center for Biological Mod-
ulators of the 21st Century Frontier R&D Program, Ministry of Edu-
cation, Science and Technology, Korea.

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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.12.035.
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