Synthesis and 11β hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group

Article abstract of DOI:10.1016/j.bmcl.2010.10.123

A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11β-HSD1, selectivity toward 11β-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11β-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.

Full text of DOI:10.1016/j.bmcl.2010.10.123

Bioorganic & Medicinal Chemistry Letters 21 (2011) 435–439
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and 11b hydroxysteroid dehydrogenase 1 inhibition
of thiazolidine derivatives with an adamantyl group
Sung Wook Kwon a, , Seung Kyu Kang b, , Jae Hong Lee a, Joo Hwan Bok b, Chi Hyun Kim b, Sang Dal Rhee b,
Won Hoon Jung b, Hee Youn Kim b, Myung Ae Bae b, Jin Sook Song b, Duck Chan Ha a, Hyae Gyoung Cheon b,
b,
Ki Young Kim b, , Jin Hee Ahn
⇑
⇑
a Department of Chemistry, Korea University, Seoul 136-701, 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 thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their
ability to inhibit 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1). Our initial compound 5a showed a
weak inhibitory activity. Significant improvements in potency were achieved by substituent modifica-
tion. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11b-HSD1,
selectivity toward 11b-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this
compound significantly inhibited 11b-HSD1 activity in rat and monkey models, and showed improved
glycemic control in KKAy mice.
Received 31 July 2010
Revised 8 October 2010
Accepted 25 October 2010
Available online 2 November 2010
Keywords:
Diabetes
11beta-HSD1
Thiazolidine
Adamantyl
Ó 2010 Elsevier Ltd. All rights reserved.
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 relationship 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
resistance.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.
A series of thiazolidine derivatives with an adamantyl group
was synthesized according to Schemes 1 and 2. Cysteamine hydro-
chloride was cyclized using ethyl glyoxalate in toluene to provide
ethyl thiazolidine-2-carboxylate 1. After Boc-protection, N-Boc
protected thiazolidine ester was hydrolyzed with LiOH to yield
the corresponding acid 2. This compound was subsequently cou-
pled with 2-adamantylamine to afford compound 3, which was
deprotected by 4 M HCl and further derivatized with diverse elec-
trophiles to afford thiazolidine derivatives with an adamantyl
group (5).
Compound 1 was derivatized with sulfonyl chlorides or benzyl
bromide to yield the compound 6, which was hydrolyzed and ami-
dated with substituted adamantyl amines to finally produce 8.
Racemic ethyl thiazolidine-2-carboxylate 1 was converted to the
During the last few years, several classes of 11b-HSD1 inhibitors
have been reported.6–12 Among the classes of 11b-HSD1 inhibitors,
adamantyl group is one of the most popular and promising skele-
tons.9–12 Therefore, we searched our chemical library for a new
11b-HSD1 inhibitor with an adamantyl group and adamantyl thia-
zolidine-2-carboxamide (5a) was discovered as a hit (Fig. 2).
We now wish to report the synthesis of thiazolidine derivatives
with an adamantyl group and their biological evaluation as
11b-HSD1 inhibitors.
chiral compound 9 through crystallization induced dynamic
resolution using tartaric acid.13 The next steps were to derivatize
OH
OH
OH
O
O
O
OH
HO
11β HSD1
H
H
H
H
H
H
O
O
⇑
Corresponding authors. Tel.: +82 42 860 7076; fax: +82 42 860 7160 (J.H.A.).
E-mail address: jhahn@krict.re.kr (J.H. Ahn).
cortisone
cortisol
Authors contributed equally.
Figure 1. The role of 11b-HSD1 between cortisone and cortisol.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.123

436
S. W. Kwon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 435–439
H
O
N
HN
S
Figure 2. Chemical structure of 5a.
O
O
OH
OEt
a
HCl
H2N
b,c
Boc
SH
N
HN
S
S
2
1
d
g
O
O
7
H
O
OEt
OH
N
R1
N
R1
c
Boc
N
N
S
S
h
S
e
6
3
R = sulfonyl or benzyl
H
O
H
O
5
N
N
R2
H
O
HCl
HN
R1
N
f
R1
N
S
S
N
S
8
4
R1 = benzene sulfonyl, benzoyl, phenyl carbamoyl)
R2 = OH, CO2Me, CONH2
Scheme 1. Reagents and conditions: (a) ethyl glyoxalate, NaHCO3, toluene, H2O, 5 °C to room temperature, 16 h; (b) (Boc)2O, CH2Cl2, room temperature, 12 h; (c) LiOH, H2O,
MeOH, THF, room temperature, 4 h; (d) 2-adamantylamine, EDCI, HOBT, DIPEA, i-PrOH, room temperature; (e) 4 M HCl in 1,4-dioxane, CH2Cl2, room temperature, 12 h;
(f) R-X, DMAP, TEA, CH2Cl2, 4 h; (g) R-X, DMAP, TEA, CH2Cl2, 4 h or K2CO3, acetone, reflux, 3 h; (h) adamantylamines, EDCI, HOBT, DIPEA, DMSO, i-PrOH, room
temperature, 5 h.
11b-HSD1 were incubated with cortisone, and chemical com-
O
1
O
9
R2
H
N
pound. The IC50 values of compounds were determined from con-
centration-dependent inhibition curves. Carbenoxolone was used
as a reference compound.14
O
OEt
OEt
a
b,c
R1
HN
HN
N
S
S
S
Thaizolidine-2-carboxylic acid adamantylamide 5a was identi-
fied as a hit with an IC50 value of 2.13
effects of nitrogen on thiazolidine were evaluated as shown in
Table 1. N-Boc substituted thiazolidine (5b, IC50 = 0.554 M) was
lM. First, the substituent
8
l
R1 = sulfonyl or arylakyl
R2 = H, CONH2
found to be nearly four times greater than that of compound 5a.
In addition, the in vitro potency of the benzoyl derivative 5c was
nine times better than compound 5b with an IC50 value of
63 nM. However, the activity of the urea compound 5d was signif-
icantly reduced. Although benzyl derivatives 5e showed good
inhibitory activity (IC50 = 20 nM), sulfonyl derivatives 5f exhibited
the best in vitro potency among the compounds of this series with
an IC50 value of 10 nM. Therefore, sulfonyl derivatives were further
investigated. Sulfonyl derivatives with electron donating groups
such as methyl and methoxy (5g and 5h) showed similar or weaker
inhibitory activity than unsubstituted phenyl derivative. Further-
more, t-butylphenyl sulfonyl substituent seemed to be detrimental
to the inhibitory activity (5i). Introduction of fluoride and chloride
resulted in good in vitro potencies around 10 nM (5k–5m). Among
Scheme 2. Reagents and conditions: (a) (i) D-tartaric acid, ethanol, diethyl ether,
5 days; (ii) 10% sodium bicarbonate, ether, 10 °C; (b) (i) R-X, DMAP, TEA, CH2Cl2,
4 h; (ii) LiOH, H2O, MeOH, THF, room temperature, 4 h; (c) 2-adamantyl amine or N-
[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]amine, EDCI, HOBT, DIPEA, DMSO,
i-PrOH, room temperature, 5 h.
compound 9 with N-substitution and amidation with adamantyl
derivatives including N-[5-(aminocarbonyl)tricycle[3,3,1,13,7]-
dec-2-yl]amine to afford a variety of isomers 8 including R/S at
the 2-position of thiazolidine and E/Z at the adamantyl group.
The in vitro inhibitory activity of 11b-HSD1 was assessed with
the use of a HTRF cortisol assay. CHO cells overexpressing human

S. W. Kwon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 435–439
437
Table 1
Table 2
In vitro human 11b-HSD1 inhibitory activity of thiazolidine derivatives with
adamantyl group
In vitro human 11b-HSD1 inhibitory activity of sulfonyl
thiazolidine derivatives with adamantyl group
a
Compound
Structure
IC50
(
lM)
Cl
H
N
R2
H
N
O
N
O
Cl
O
S
O
5a
2.13
HCl
HN
S
S
H
N
a
Compound
R2
IC50 (lM)
O
N
O
O
5b
5c
0.554
0.063
5m
8a
8b
8c
H
OH
CO2Me
CONH2
0.010
0.683
0.170
0.005
S
H
O
N
a
O
IC50 values were determined by GraphPad Prism
software.
N
S
H
N
Table 3
O
N
In vitro 11b-HSD1 inhibitory activity of sulfonyl thiazolidine derivatives with
adamantyl group
O
5d
5e
0.945
0.020
S
N
H
NH2
H
H
N
O
N
N
O
N
O
R1
S
S
a
a
Compound
R1
hHSD1 IC50
(nM)
mHSD1 IC50
(nM)
H
O
N
N
O
S
O
5f
5g
5h
5i
0.010
0.020
0.055
0.149
0.020
0.010
0.010
Cl
O
S
S
8c
5
6
Cl
O
H
N
O
N
O
O
S
S
8d
8e
8f
67
8
842
57
S
O
O
O
S
H
N
MeO
O
O
O
O
S
S
O
N
S
MeO
16
171
O
H
F
O
N
O
S
O
S
O
8g
8h
4
4
N
S
O
F
F
H
N
O
F
O
N
11
76
S
O
5j
O
S
S
O
O
O
S
8i
11
27
H
N
O
O
Carbenoxolone
500
250
5k
5l
S
O
N
S
a
IC50 values were determined by GraphPad Prism software.
F
H
Cl
O
N
Hydroxy-adamantyl analog (8a) showed a weak in vitro activity
with an IC50 value of 683 nM. Also, methoxycarbonyladamantyl
derivative (8b) exhibited a moderate potency (170 nM). Fortu-
nately, amide derivative (8c) showed the best in vitro activity with
an IC50 value of 5 nM. From these results, we selected the carba-
moyladamantyl group for further derivatization.
Thiazolidine derivatives with a carbamoyladamantyl group
were evaluated for their in vitro potency against human and mouse
cell lines and the results are summarized in Table 3. 3,4-Dic-
hlorophenylsulfonyl derivative 8c showed good in vitro potency
in both human and mouse cell lines with an IC50 value of 5 and
6 nM, respectively. However, the unsubstituted phenyl compound
8d exhibited a relatively weak activity in human as well as mouse
O
S
N
S
O
Cl
H
N
Cl
O
N
5m
O
S
0.010
0.5
S
O
Carbenoxolone
a
IC50 values were determined by GraphPad Prism software.
them, we chose 5m to further evaluate the functionalized adaman-
tyl amide derivatives and the results are summarized in Table 2.

438
S. W. Kwon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 435–439
Table 4
In vitro human 11b-HSD1 inhibitory activity of sulfonyl thiazolidine derivatives with
adamantyl group
a
Compound
Structure
IC50
(
lM)
NH2
H
N
F
O
N
8g (E/Z)
0.004
0.003
O
S
O
S
O
NH2
H
N
F
O
N
8g (E)
O
S
O
S
O
O
O
O
NH2
H
N
8g (Z)
7.95
F
O
N
O
S
S
O
NH2
NH2
NH2
H
N
F
O
N
8g (S) (E)
8g (S) (Z)
8g (R) (E)
8g (R) (Z)
10
0.012
O
S
O
S
O
NH2
H
N
38.7
F
O
N
O
S
S
O
H
N
F
O
N
Figure 3. Anti-diabetic efficacy of compound 8g (E) in KKAy mice. (a) Non-fasting
blood glucose levels; (b) glucose level after an oral glucose tolerance test; (c)
glucose AUC determined from 0 to 120 min. Results are expressed as means SEM
0.002
1.34
O
S
O
S
O
*
**
for n = 7 mice/group. P <0.05, P <0.01.
NH2
azolidine showed higher in vitro potency when compared with
S-configuration. Compound [8g (R) (E)] combining an R-configura-
tion at the 2-position of thiazolidine and an E-isomer at the
adamantyl group exhibited the highest activity, with an IC50 value
of 2 nM. The in vitro potency of proline derivatives (10 and 11) was
tested. (R)-Isomer (10) showed better activity than (S)-isomer (11)
with IC50 value of 10 nM. Although the proline derivatives also
showed relatively high in vitro potency, the thiazolidine derivative
exhibited an even higher potency.
H
N
F
O
N
O
S
S
O
H
N
F
O
N
0.037
O
S
O
O
We chose three representative compounds (8c, 8e, and 8g (E))
for further biological evaluations, which covered selectivity, micro-
somal stability, hERG, CYP assay, PK, and in vivo study. According
to Table 5, compounds 8c, 8e, and 8g (E) exhibited a good selectiv-
ity toward 11b-HSD2. Furthermore, compounds 8e and 8g (E)
showed acceptable liver microsomal stability, no hERG binding
and CYP inhibition. Also pharmacokinetic (PK) and in vivo
11b-HSD1 inhibition study in inguinal fat and liver tissues were
performed. Compound 8g (E) exhibited reasonable PK profile and
in vivo inhibition of approximately 65–67% in inguinal fat and liver
tissues.
Compound 8g (E) was dosed orally in KKAy mice, displayed
significant higher blood glucose level compared with its lean litter-
mates (C57BL6j mice), at 100 mg/kg for 18 days. The non-fasting
blood glucose level was reduced by 28.2% compared with vehicle
mice after 18 days (Fig. 3a). The oral glucose tolerance test (OGTT)
was performed after 18 days. The plasma glucose levels,
determined on the basis of AUC of the glucose concentration, were
reduced by 18.1% compared to vehicle (Fig. 3b and c).
NH2
H
N
F
O
N
11
0.010
0.5
O
S
O
O
Carbenoxolone
a
IC50 values were determined by GraphPad Prism software.
cell lines (67 and 842 nM, respectively). Tosyl derivatives showed
IC50 value of 8 nM in human cell lines. Lastly, the 2-fluor-
ophenylsulfonyl derivative 8g was the most active in this series
with an IC50 value of 4 nM in both the human and mouse system.
Compound 8g has several isomers including the E/Z isomer at
the adamantyl group and R/S isomer at the 2-position of thiazoli-
dine. Therefore, we synthesized each isomer and evaluated their
activities as shown in Table 4. E-Isomer [8g (E)] of compound 8g
showed better activity than the E/Z mixture (8g). Whereas, the
Z-isomer [8g (Z)] of 8g exhibited a very weak in vitro inhibitory
activity. The thiazolidine derivative with R at the 2-position of thi-

S. W. Kwon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 435–439
439
Table 5
In vitro inhibition, metabolic stability, hERG, and PK study of thiazolidine derivatives
Entry
hHSD1
IC50 (nM)
mHSD1
IC50 (nM)
hHSD2
IC50 (nM)
Microsomal
stability
hERG
CYP inhibition %
at 10
PK (rat)
In vivo 11b-HSD1
inhibition
a
a
a
l
M
30 min after
8c
8e
2
8
6
57
47% at 10
l
M
M
43% (h)
53% (h)
0% at 10
l
>100
>100
l
M
M
1A2 0%
2C19 21%
2D6 0%
3A4 24%
1A2 0%
PO Cmax = 0.65 g/mL
Cl (L/h/Kg) = 2.6 F = 16%
PO
(40mpk)
F (51%)
L (51%)
PO
8g (E)
3
3
0% at 10
l
M
77% (h)
l
PO Cmax = 1.2 g/mL PO
2C19 25%
2D6 0%
3A4 21%
AUC0–8 h = 1.11
(L/h/Kg) = 2.9 F = 32%
l
g h/mL Cl
(40mpk)
F (67%)
L (65%)
a
IC50 values were determined by GraphPad Prism software.
Table 6
References and notes
Ex vivo pharmacodynamic data of compound 8g (E)a
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62%
% inhibition of HSD1 in liver 2 h
57%
a
Compound was administered at 20 mg/kg oral.
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In conclusion, we have identified a series of thiazolidine deriv-
atives with an adamantyl group as 11b-HSD1 inhibitors. Our initial
compound 5a showed a weak inhibitory activity. Significant
improvements in its potency were achieved by substituent modifi-
cation. In particular, compound 8g (E) showed good in vitro
inhibitory activity toward human 11b-HSD1, selectivity toward
11b-HSD2, metabolic stability, good PK, and safety profile such as
hERG and CYP. Further, this compound significantly inhibited
11b-HSD1 activity in rat and monkey models, and showed
improved glycemic control in KKAy mice.
Acknowledgments
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Education, Science and Technology, and the Ministry of Knowledge
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.10.123.