Adamantyl carboxamides and acetamides as potent human 11β- hydroxysteroid dehydrogenase type 1 inhibitors

Article abstract of DOI:10.1016/j.bmc.2012.08.056

The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC₅₀ values in the 100 nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC₅₀ = 114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC₅₀ = 280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.

Full text of DOI:10.1016/j.bmc.2012.08.056

Bioorganic & Medicinal Chemistry 20 (2012) 6394–6402
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Adamantyl carboxamides and acetamides as potent human
11b-hydroxysteroid dehydrogenase type 1 inhibitors
Xiangdong Su a, Heather A. Halem b, Mark P. Thomas a, Cecile Moutrille a, Michael D. Culler b,
Nigel Vicker a, Barry V. L. Potter a,
⇑
a Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
b IPSEN, Biomeasure Inc., 27 Maple Street, Milford, MA 01757, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The modulation of 11b-HSD1 activity with selective inhibitors has beneficial effects on various metabolic
disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series
of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11b-HSD1 in
HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11b-
HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC50 values in the 100 nM range. These
compounds are also highly selective 11b-HSD1 inhibitors with no activity against 11b-HSD2 and 17b-
HSD1. Compound 15 (IC50 = 114 nM) with weak inhibitory activity against the key human cytochrome
P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further
development. Importantly, compound 41 (IC50 = 280 nM) provides a new lead that incorporates an ada-
mantyl group surrogate and should enable further series diversification.
Received 19 June 2012
Revised 20 August 2012
Accepted 24 August 2012
Available online 12 September 2012
Keywords:
Hydroxysteroid dehydrogenase
11b-HSD1 inhibitor
Adamantyl amide
Diabetes
Ó 2012 Elsevier Ltd. All rights reserved.
Structure–activity relationship
1. Introduction
production, antagonises insulin secretion from pancreatic b-cells
and insulin-mediated glucose uptake in peripheral tissues.9
11b-Hydroxysteroid dehydrogenase isozymes catalyze the
intracellular conversion of inert 11-keto glucocorticoids to physio-
logically active glucocorticoids in specific tissues, and vice versa.
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) functions
as an NADPH-dependent reductase converting cortisone (1) in hu-
mans to the active glucocorticoid cortisol (2) (Scheme 1). This endo-
plasmic reticulum-associated enzyme is highly expressed in liver,
adipose tissue and in the central nervous system. 11b-HSD1 medi-
ates the pre-receptor activation of cortisone, which provides a
mechanism for specific tissues to produce intracellular, non-adre-
nal cortisol, thereby locally amplifying glucocorticoid action.1–3
Conversely, 11b-hydroxysteroid dehydrogenase type 2 (11b-
HSD2) is an exclusively NAD+ dependent enzyme that catalyzes
the transformation of cortisol to inactive cortisone. As the enzyme
is highly expressed in mineralocorticoid target tissues, its gluco-
corticoid inactivation function prevents cortisol occupying the
mineralocorticoid receptor (MR) which may lead to sodium reten-
tion, hypokalemia and hypertension.4,5
The relationship of 11b-HSD1 mediated glucocorticoid regula-
tion with metabolic disorders, such as obesity and type 2 diabetes
has been well established by studies using genetically- modified
rodent models. 11b-HSD1 knock-out mice resist diet-induced
obesity and stress induced hyperglycaemia. These animals also
have decreased cholesterol and triglyceride levels.2,10,11 In con-
trast, transgenic mice that overexpress 11b-HSD1 in fat tissues de-
velop symptoms of insulin-resistant diabetes, hyperlipidemia and
visceral obesity.12,13
The strategy of treating phenotypes of metabolic syndrome
with selective 11b-HSD1 inhibitors has attracted considerable
interest over the last decade. The discovery of various structural
types of selective and potent 11b-HSD1 inhibitor has been exten-
sively reviewed.14–17 Several crystal structures of 11b-HSD1 with
different ligands have been published.18
Preclinical studies show that modulation of 11b-HSD1 activity
with selective inhibitors has beneficial effects on various metabolic
disorders including insulin resistance, dyslipidemia and obes-
ity.13,19–21 During recent years, clinical studies have been conducted
for several 11b-HSD1 inhibitors, including Pfizer’s PF-915275,
Amgen’s AMG-221, AstraZeneca’s AZD-4017, Merck’s MK-0736,
MK-0916 and Incyte’s INCB013739. The mid-stage study of
INCB013739 demonstrated that treatment of type 2 diabetes melli-
tus patients with INCB013739 for 28 days significantly improved
hepatic and peripheral insulin sensitivity and reduced fasting
Excessive glucocorticoid action has been implicated in the
development of several phenotypes associated with metabolic syn-
drome, such as obesity and type 2 diabetes.6–8 Studies show that
glucocorticoid receptor (GR) activation stimulates hepatic glucose
⇑
Corresponding author.
E-mail address: B.V.L.Potter@bath.ac.uk (B.V.L. Potter).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.08.056

X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
6395
OH
OH
OH
OH
O
O
O
O
m
a or b
O
HO
X
N
R
Ar
β
11 -HSD1
n
n
11β-HSD2
X = Cl or OH
n = 0 or 1
m = 1 or 2
O
O
1 Cortisone
2 Cortisol
Scheme 2. Synthesis of adamantyl carboxamides and acetamides. Reagents and
conditions: (a) X = Cl, amine, Et3N/DCM, rt; (b) X = OH, amine, EDCI, DMAP, Et3N/
DCM, rt.
Scheme 1. Interconversion of glucocorticoid catalyzed by 11b-HSDs.
plasma glucose, plasma low density lipoprotein and total choles-
terol levels.22,23
To indentify novel 11b-HSD1 inhibitors, we have previously
synthesized series of adamantyl ethanone compounds, and discov-
ered several selective potent inhibitors.24–26 Our previous studies
also identified compounds with a thiophene ring attached to an
adamantyl moiety through an amide linker that possess high
inhibitory activity against human 11b-HSD1. Compounds 3 and 4
(Fig. 1) exhibit inhibition of 11b-HSD1 with IC50 values in the
200-300 nM range when tested in the HEK-293 cell line transfected
with the human 11b-HSD1 gene.27 We performed further optimi-
zation on these hit compounds by varying the aromatic region
and linker. Target compounds were screened for their inhibitory
activity against human 11b-HSD1 in a HEK293 cell based assay.28
Potent 11b-HSD1 inhibitors were also examined for their selectiv-
ity over human 11b-HSD2 and 17b-hydroxysteroid dehydrogenase
type 1 (17b-HSD1), one of the alcohol oxidoreductases that cata-
lyze the NADPH-dependent reduction of estrone to estradiol.29
Here we report the synthesis and the structure–activity relation-
ships of some adamantyl carboxamide and adamantyl acetamide
compounds as potent inhibitors of 11b-HSD1.
Table 1
Human 11b-HSD1 inhibition by adamantyl carboxamide derivatives 3, 5–19
R
N
Ar
O
Compd.
R
Ar
IC50 (nM)
229
S
S
S
∗
3
Me
∗
5
6
H
403
275
*
Me
S
*
7
Me
12%a
H2N
2. Results and discussion
S
*
*
*
8
9
Me
H
55%a
8%a
2.1. Synthesis of target compounds
S
Target compounds with an adamantyl group were synthesized
from 1-adamantyl carbonyl chloride or 1-adamantyl acetic acid
through an amide coupling reaction with various amines under
standard conditions as illustrated in Scheme 2. Amines were either
purchased or made by reductive amination from the corresponding
aldehyde derivatives.
S
S
10
11
12
13
14
Me
Me
Me
Me
H
32%a
29%a
125
Cl
*
∗
S
2.2. Structure–activity relationship
O
O
*
*
249
11b-HSD1 inhibition was measured in intact human HEK-293
cells to reveal the true inhibitory activity. Differences in observed
effects for different compounds may reflect combinatorial factors
including the ability to penetrate the cell membrane, the stability
within the cell and the binding ability to the enzyme.
Our previous study found a pharmacophore template that con-
sists of a thiophenyl ring attached to an adamantyl moiety through
an amide linker. The adamantyl group, being highly hydrophobic,
has been identified as a popular moiety in different structural
combinations for 11b-HSD1 inhibition.30–32 Compounds 3 and 4
(Fig. 1) exhibit inhibition of 11b-HSD1 with IC50 values in the
200–300 nM range. Further optimization was performed based
on these compounds.
68%a
N
N
N
15
16
Me
H
114
*
*
1700
17
Me
24%a
*
N
18
19
Me
Me
34%a
31%a
N
S
*
*
N
O
N
S
3 n= 0
IC50= 229 nM
N
n
4 n = 1 IC50= 308 nM
‘⁄Indicates point of attachment.’
a
Percentage of inhibition measured at 1 lM.
Figure 1. Adamantyl amides as 11b-HSD1 inhibitors.

6396
X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
The substituent effects on the thiophenyl ring were evaluated
to generate a compound with significant inhibitory activity. The
pyridyl derivatives 24–27 only exhibit poor to modest activity
Table 2.
Compounds with a more flexible tethering were also synthe-
sized and evaluated for their activity. (Table 3). The thiophenyl
derivative (28) has only half the potency of compound 3. However,
the 2-pyridyl compound (30) exhibits a significant inhibition with
an IC50 value of 165 nM, suggesting that the flexible linker is more
suitable for a pyridyl derivative.
with compounds 6–11 Table 1. The 3-methyl derivative 6 retains
nearly the same activity as parent compound 3. However, the
amino group substitution at the same position (7) causes a sharp
decrease of activity, suggesting that a basic and hydrophilic substi-
tution is not favoured in that area. Moving the methyl substituent
to the 4- or 5-position affords compounds 8 or 10, respectively.
These compounds show only weak inhibition for 11b-HSD1 at a
concentration of 1 lM, as does the compound with 5-chloro substi-
tuent (11). Compared with the 2-thiophenyl compound (3), the
3-thiophenyl analogue (12) exhibits an increased activity with an
IC50 value of 125 nM.27
In the adamantyl acetamide series, the 2-thiophenyl compound
(4) is only slightly weaker than the corresponding adamantyl
amide (3), while the 3-thiophenyl derivative 34 exhibits a greater
than 2-fold reduction in potency compared to 12.27 Furthermore,
the 2-pyrrolyl derivative (35) with an IC50 of 655 nM loses nearly
6-fold inhibitory activity compared with 2-pyrrolyl compound 15
(IC50 = 114 nM) in the amide series. It is also observed in the acet-
amide series that the N-methyl compounds 4 and 35 possess rela-
tively higher potency than their respective NH analogues 33 and 36
Table 4.
The effect of using another 5-membered heterocycle to replace
the thiophenyl ring was investigated Table 1. The 2-furanyl deriv-
ative (13) with an IC50 at 249 nM has about the same potency as
3.27 The 1-methyl-1H-2-pyrrolyl compound (15) with an IC50 of
114 nM exhibits a twofold higher potency than 3. It is assumed
that the pyrrolyl ring can form further interactions with the en-
zyme and/or alters the geometry of the molecule placing the ada-
mantyl and/or the aromatic ring in a position to gain further
binding in the active site. Replacing the thiophenyl group with a
1-methyl-1H-imidazolyl, 1-methyl-1H-pyrazolyl or 4-methyl-
thiazolyl group generated compounds 17–19. None of these com-
Therefore, compound 15 is an interesting lead for further opti-
mization and development in this class of inhibitors.
We have previous discovered that a substituted phenyl group
may potentially be used as a replacement for the adamantyl
group.33 We therefore pursued the synthesis of a set of polycyclic
or substituted aliphatic cyclic compounds in the carboxamide ser-
ies Table 5. The noradamantyl derivative (39) with an IC50 of
1080 nM was nearly fivefold less active than the adamantyl ana-
logue 3, although these two compounds have very similar molecu-
lar shape and properties. The (p-tolyl)cyclopropyl compound (41,
IC50 = 280 nM) exhibits 11b-HSD1 inhibitory activity at the same
potency as compound 3, suggesting the possibility to be used as
a replacement for adamantyl group. It is interesting to note that
4-chlorophenylcyclopropyl compound (42) shows a loss of activity
pounds shows significant inhibitory activity at 1 lM.
It was found that the N-methyl amide analogue usually exhibits
higher potency than the corresponding NH analogues; for example,
compound 3 is almost twice as active as 5, while compound 15 is
over 15 times more potent than 16.
In the six-membered aromatic ring series, the 3-amino substi-
tuted benzene derivative (20) exhibits an IC50 value of 118 nM,
suggesting that the NH2 group may enable more favourable inter-
actions with the enzyme. On the other hand, the acetamido-,
methyl- or chloro- substitution at the same position (21–23) fails
of ꢀ5.5-fold with an IC50 of only ꢀ1.6
lM, in comparison with 41;
however, cyclobutyl analogue (43) achieves an improved activity
Table 2
with an IC50 value at 385 nM.
All potent compounds were evaluated for their selectivity over
11b-HSD2 and 17b-HSD1 enzymes. They exhibit no inhibitory
activity at 10 lM.
To identify potential problems with these compounds interfer-
ing with the metabolism of other drugs, compounds 3, 4, 15 and 41
Human 11b-HSD1 inhibition by adamantyl carboxamide derivatives 20–27
R
N
Ar
O
Compd.
R
Ar
IC50 (nM)
118
Table 3
Human 11b-HSD1 inhibition by adamantyl carboxamide derivatives 28–32
NH2
*
20
Me
R
N
NHAc
*
*
Ar
21
22
23
Me
Me
Me
22%a
23%a
17%a
O
Compd.
28
R
Ar
IC50 (nM)
448
Cl
*
S
S
∗
Me
H
∗
24
25
Me
H
57%a
676
∗
29
679
N
∗
*
30
31
Me
H
165
379
N
*
N
N
*
26
27
H
45%a
48%a
N
∗
N
*
32
H
1%a
Me
N
‘⁄Indicates point of attachment.’
‘⁄Indicates point of attachment.’
a
a
Percentage of inhibition measured at 1 lM.
Percentage of inhibition measured at 1
l
M.

X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
6397
Table 4
Table 6
Human 11b-HSD1 inhibition by adamantyl acetamide derivatives 4, 33–38
Inhibition of human cytochrome P450 enzymes
CYP450
Compound
O
3
4
15b
41b
N
R
Ar
1A2
2C9
2C19
2D6
3A4-BFC
3A4-BQ
6%a
1%a
>100
>100
>100
>100
l
l
l
l
M
M
M
M
>100 lM
62%a
13%a
2%a
49%a
80%a
9%a
4.5
lM
>100
lM
72 lM
10
l
Mb
0.15
l
Mb
19
18
l
M
7.3
lM
34%a
66%a
lM
1.6
lM
Compd.
R
Ar
IC50 (nM)
308
a
S
S
Percentage inhibition measured at 10
IC50 reported as the mean value of two measurements.
l
M.
∗
4
Me
H
b
∗
∗
33
66%a
34
35
Me
Me
349
655
S
N
N
*
36
H
*
2880
∗
37
38
Me
Me
67%a
26%a
N
*
N
‘⁄Indicates point of attachment.’
a
Percentage of inhibition measured at 1 lM.
Table 5
Human 11b-HSD1 inhibition by non-adamantyl compounds 39–44
O
S
N
R
Compd.
R
IC50 (nM)
39
40
41
1080
3600
280
∗
∗
∗
∗
42
43
44
Cl
Cl
Cl
1550
385
∗
∗
2200
‘⁄Indicates point of attachment.’
Figure 2. Docking solutions for compounds 3 (top), 6 (middle) and 12 (bottom), all
in cyan, with the cofactor in pink and the active site residues in green.
were studied for their inhibition of the key human cytochrome
P450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4-BFC (7-benzyloxy-4-(tri-
fluoromethyl)coumarin) and 3A4-BQ (7-benzyloxyquinoline) (Ta-
ble 6). Compound 3 displays weak activity against 2C9 and 3A4-
BFC, while the acetamide analogue (4) strongly inhibits 3A4-BFC
(IC50 = 150 nM). Nevertheless, compound 15, one of the most po-
tent 11b-HSD1 inhibitors in this series, exhibits very weak inhibi-
tion for these cytochrome P450 enzymes. The non-adamantyl
compound 41 shows a moderate inhibition of 2CA, 3A4-BFC and
NADPH to evaluate their stability under such conditions. The
remaining parent compound was measured using a HPLC method.
Both 3 and 15 are moderately stable under such condition with a
T1/2 value from 60 to 70 min.
Compound 3 was studied for its membrane permeability using
the Caco-2 cell model. The apparent permeability coefficient (Papp
)
3A4-BQ with IC50 values from 1.6 to 7.3 lM.
from apical to basolateral side was measured at a concentration of
Potent inhibitors (3 and 15) were incubated at 37 °C for 40 min
with human liver microsomes in the presence of the cofactor
20 lM; and the result shows that the compound is of high perme-
ability (Papp (A>B) = 3.3 Â 10À5).

6398
X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
being ꢀ3.5 Å from Tyr177 may form a stacking interaction with the
residue (Fig. 3, top). On the other hand, docking studies of com-
pound 20 show that the top 5 poses position the phenyl ring in
the hydrophobic pocket close to the cofactor. The amino group,
being 2.9 Å away from Thr124, possibly forms added hydrogen
bond interactions. With the ‘reversed’ orientation, the adamantyl
group fits into the pocket formed by Ser170, Ala172, Tyr177 and
Val180 (Figure 3, middle). The best docking solutions for com-
pound 30 also adapted to the ‘reversed’ position with the adaman-
tyl group forming edge-on interactions with Tyr177 (3.7 Å), and
the carbonyl group may form hydrogen bond interactions with
the catalytic residue Tyr183 (2.8 Å) and Ser170 (3.4 Å) (Fig. 3,
bottom).
3. Conclusion
Series of adamantyl carboxamide and acetamide derivatives
were synthesized and their ability to inhibit human 11b-HSD1
was evaluated on a HEK-293 cell line stably transfected with the
HSD11B1 gene. Based on the initially identified 11b-HSD1 inhibitor
(3) further optimization in the aromatic region, the carbon tether-
ing and adamantyl group in the molecule led to the discovery of
potent inhibitors with an IC50 value in the 100 nM range. The po-
tent compounds are also highly selective 11b-HSD1 inhibitors with
no activity against 11b-HSD2 and 17b-HSD1. Compound 15 exhib-
its very weak inhibitory activity against the key human cyto-
chrome P450 enzymes, indicating that it is unlikely for the
compound to interfere with metabolism of other drugs. In addition,
the compound is also relatively stable when incubated with human
liver microsomes. Compound 41 also offers a potent lead for fur-
ther development with a (p-tolyl)cyclopropyl surrogate for the
adamantyl group.
4. Experimental
4.1. 11b-HSD1 inhibition assay protocol: human HEK-293 cell
based assay
The cell-based assays were conducted on the human HEK-293
cell line stably transfected with the HSD11B1 gene.28 11b-HSD1
activity was determined by measuring the amount of tritiated
product formed using a scintillation proximity assay (SPA).
Cells were incubated in 96-well micro-plates in the presence of
tritiated cortisone substrate and the assay plates contained inter-
nal high and low controls to allow calculation of percentage inhibi-
tion. Each well of a 96-well culture plate was seeded with human
Figure 3. Docking solutions for compounds 15 (top), 20 (middle) and 30 (bottom),
all in cyan, with the cofactor in pink and the active site residues in green.
As the inhibitory activity was studied on the whole cell, the high
permeability of the inhibitor suggests a potentially good correla-
tion between the activity and the binding affinity to the enzyme.
The GOLD docking program was used to determine possible bind-
ing poses.
11b-HSD1 overexpressed HEK293 cells in 100
the cells were 80% confluent, the medium was removed from each
well then 100
L of fresh, serum-free, medium containing 3H-cor-
lL medium. When
The top 5 docking solutions for compound 3 are almost identi-
cal. The adamantyl group is positioned in a hydrophobic pocket
close to the nicotinamide ring of the co-factor, the same orienta-
tion as in the published X-ray crystal structure. The carbonyl
group, being 2.5 Å away from the catalytic residue Tyr183, may
form a hydrogen bond interaction with the residue. The thiophene
ring is about 3.6 Å from Tyr177, suggesting an edge-on interaction
(Fig. 2, top). The best 5 docking solutions for compound 6 are all
adapted to the same conformation as that of compound 3, with
the extra methyl group being closer to the residue Tyr177 (2.6 Å)
(Figure 2, middle). The top 5 poses of compound 12 also overlap
perfectly with that of compound 3, with the exception of the sulfur
atom pointing towards the hydroxyl group of Tyr177 (3 Å), sug-
gesting a further hydrogen bond interaction (Figure 2, bottom).
The top docked conformation of compound 15 is very similar to
that of 3 with the adamantyl group close to the NADP. The oxygen
of the amide carbonyl group is positioned to form hydrogen bond
interactions with Tyr183 (2.7 Å) and Ser 170 (3 Å). The pyrrole ring,
l
tisone (22 nM) and test compound in 1% DMSO was added. The
control wells were also dispensed. The high control wells did not
contain compound, while low controls did not contain cells. The
plate was incubated at 37 °C for 2 h, after which 50
was removed from each well and transferred to a microplate con-
taining 100 L of a pre-incubated mixture of anti-cortisol antibody
lL of medium
l
and SPA bead. The mixture was incubated with gentle shaking until
equilibrium was reached, before transferring to a scintillation
counter to establish the enzyme activity in each sample.
The compounds were initially tested at a concentration of 1
Those compounds showing over 70% inhibition of 11b-HSD1 at
M were subjected to an IC50 measurement. A Merck compound
lM.
1
l
544 was used as the reference compound in the assay
(IC50 = 50 20 nM).19 The IC50 values are reported as the mean va-
lue of 3 measurements with variance less than 20%. IC50 values
were calculated from the dose-response curve using Microsoft

X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
6399
Excel add-in XLfit with a Four Parameter Logistic nonlinear regres-
sion model.
After stirring at ambient temperature for another 2 h, the mixture
was filtered and evaporation of the solvent gave a residue that was
purified by flash chromatography (ethyl acetate-DCM gradient elu-
tion) to give the desired carboxamide derivatives.
4.2. 11b-HSD2 and 17b-HSD1 inhibition assay protocol
11b-HSD2 activity was measured in whole Chinese hamster
ovary (CHO) cells stably transfected with the HSD11B2 gene. Cells
were incubated in 96-well microplates in the presence of tritiated
cortisol (22nM) with or without the inhibitor to be tested. After
incubation at 37 °C for 2 h, the mixture was extracted with ethyl
acetate. Enzyme activity was determined by measuring the
amount of tritiated product using thin layer chromatography
(Chloroform/Ethanol 92:8 v/v) with a PhosphorImager.
17b-HSD1 inhibition assay was performed according to the lit-
erature procedure.29
4.4.2. General method B for the preparation of acetamide or
carboxamide derivatives 33–44
To a solution of the corresponding carboxylic acid (0.5 mmol) in
DCM (8 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-car-
bodiimide (EDCI, 0.6 mmol), 4-(dimethylamino) pyridine (DMAP,
10 mg) and triethylamine (0.1 mL) at room temperature. After stir-
ring for 0.5 h, the corresponding amine (0.5 mmol) was added to
the reaction mixture. After 12 h the mixture was partitioned
between DCM and brine and the organic layer was washed with
brine, dried over MgSO4 and concentrated in vacuo. The crude prod-
uct was purified with flash chromatography (Ethyl acetate-DCM
gradient elution) to give the target acetamide or carboxamide.
4.3. Molecular modelling
Selected ligands were docked into the human 11b-HSD1 protein
X-ray crystal structure 2ILT34 using the GOLD docking program in
version 5.1 of the GOLD suite with default settings in the presence
of the cofactor. The binding site was defined as a sphere of 10 Å ra-
dius around the centroid of the ligand in the 2ILT structure. Each
ligand was docked 25 times. The Goldscore scoring function was
used to rank the ligands in order of fitness to generate the best
poses of the ligand in the active site. The five most highly ranked
poses of each ligand were studied.
4.4.3. N-Methyl-N-((3-methylthiophen-2-
yl)methyl)adamantane-1-carboxamide (6)
A white solid was obtained in 92% yield. mp 72–73.5 °C; 1H
NMR (CDCl3) d 1.71 (6H, s), 2.04 (9H, s), 2.20 (3H, s), 3.05 (3H, s),
4.68 (2H, s), 6.77 (1H, d, J = 5.2 Hz) and 7.10 (1H, d, J = 5.2 Hz);
LC/MS (APCI) m/z 304 (M+H)+; HRMS (ESI) calcd for C18H26NOS
(M+H)+ 304.1735, found: 304.1732; HPLC tR 8.1 min (>99%).
4.4.4. N-((3-Aminothiophen-2-yl)methyl)-N-
methyladamantane-1-carboxamide (7)
4.4. Chemistry
A light yellow solid was obtained in 77% yield. mp 117–119 °C;
1H NMR (CDCl3) d 1.70 (6H, s), 2.01 (9H, s), 3.21 (3H, s), 4.34 (2H,
br, NH2), 4.47 (2H, s), 6.54 (1H, d, J = 5.3 Hz) and 6.97 (1H, d,
J = 5.5 H); LC/MS (APCI) m/z 303 (MÀH)+; HRMS (ESI) calcd for
All chemicals were purchased from either Aldrich Chemical Co.
(Gillingham, UK) or Alfa Aesar (Heysham, UK). All organic solvents
of AR grade were supplied by Fisher Scientific (Loughborough, UK).
Compounds 3–5, 12, 13, 28, 29 were synthesized according to liter-
ature procedures.27 Melting points were determined using a Stan-
ford Research Systems Optimelt MPA100 and are uncorrected.
Compounds in solid form were crystallized from dichloromethane
(DCM)-ethyl acetate solution. Thin layer chromatography (TLC)
was performed on pre-coated aluminum plates (Merck, silica gel
60 F254). Products were visualized either by UV irradiation at
254 nm and by staining with 5% w/v molybdophosphoric acid in
ethanol, followed by heating. Flash column chromatography was
performed on pre-packed columns (RediSep Rf) and gradient elu-
tion (solvents indicated in text) on the Combiflash RF system (Tele-
dyne Isco). 1H NMR spectra were recorded with a Jeol Delta
270 MHz spectrometer. Chemical shifts are reported in parts per
million (ppm, d) relative to tetramethylsilane (TMS) as an internal
standard. LC/MS spectra were performed on a Waters 2790 ma-
C
17H25N2OS (M+H)+ 305.1688, found: 305.1685; HPLC tR 2.6 min
(>98%).
4.4.5. N-Methyl-N-((4-methylthiophen-2-yl)-
methyl)adamantane-1-carboxamide (8)
A white solid was obtained in 82% yield. mp 87–88 °C; 1H NMR
(CDCl3) d 1.70 (6H, S), 2.03 (9H, s), 2.20 (3H, d, J = 1.0 Hz), 3.06 (3H,
s), 4.67 (2H, s), 6.71 (1H, s) and 6.77 (1H, q, J = 1.2 Hz); LC/MS
(APCI) m/z 304 (M+H)+; HRMS (ESI) calcd for C18H26NOS (M+H)+
304.1735, found: 304.1738; HPLC tR 8.3 min (>99%).
4.4.6. N-((4-Methylthiophen-2-yl)methyl)-adamantane-1-
carboxamide (9)
A white solid was obtained in 95% yield. mp 127–128.5 °C; 1H
NMR (CDCl3) d 1.65–1.91 (12H, m), 2.03 (3H, br), 2.20 (3H, d,
J = 1.0 Hz), 4.53 (2H, d, J = 5.4 Hz2), 5.86 (1H, br, NH) and 6.74–
6.77 (2H, m); LC/MS (APCI) m/z 288 (MÀH)+; HRMS (ESI) calcd
for C17H24NOS (M+H)+ 290.1579, found: 290.1583; HPLC tR
5.5 min (>99%).
chine with Waters ‘Symmetry’ C18 column (packing: 3.5 lm,
4.6 Â 75 mm) eluting with 10% H2O/CH3OH (1 mL/min), and de-
tected with a ZQ MicroMass spectrometer and PDA detector using
Atmospheric Pressure Chemical Ionization (APCI) or Electrospray
Ionisation (ESI). High resolution mass spectra were recorded on a
Bruker MicroTOF with ESI. HPLC was undertaken using a Waters
717 machine with Autosampler and PDA detector. The column used
was a Waters ‘Symmetry’ C18 (packing: 3.5
with an isocratic mobile phase consisting of H2O/CH3CN at a flow
rate of 1.0 mL/min.
4.4.7. N-Methyl-N-((5-methylthiophen-2-yl)-
methyl)adamantane-1-carboxamide (10)
A white solid was obtained in 73% yield. mp 83–85.5 °C; 1H
NMR (CDCl3) d 1.70 (6H, s), 2.03 (9H, s, 2.42 (3H, d, J = 1.0 Hz),
3.05 (3H, s), 4.64 (2H, s), 6.55 (1H, dq, J = 3.3, 1.0 Hz) and 6.68
(1H, d, J = 3.3 Hz); LC/MS (APCI) m/z 304 (M+H)+; HRMS (ESI) calcd
for C18H26NOS (M+H)+ 304.1735, found: 304.1731; HPLC tR 7.0 min
(99%).
lm, 4.6 Â 150 mm)
4.4.1. General method A for the preparation of adamantyl
carboxamide derivatives 6–32
To
a
solution of the 1-adamantane carbonyl chloride
4.4.8. N-((5-Chlorothiophen-2-yl)methyl)-N-
(0.50 mmol, 1.06 equiv) in DCM (5 mL) was added triethylamine
(0.15 mL), followed by the corresponding amine (0.47 mmol,
1 equiv). The reaction mixture was stirred at ambient temperature
under nitrogen overnight. PS-Trisamine (10-20 mg) was added.
methyladamantane-1-carboxamide (11)
A white solid was obtained in 74% yield. mp 92–94 °C; 1H NMR
(CDCl3) d 1.75 (6H, s), 2.01 (9H, s), 3.10 (3H, s), 4.55 (2H, s) and 6.70
(2H, AB); LC/MS (APCI) m/z 324 (M+H)+; HRMS (ESI) calcd for

6400
X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
C17H23ClNOS (M+H)+ 324.1189, found: 324.1193; HPLC tR 10.0 min
(99%).
4.63 (2H, s2), 6.89 (1H, br), 7.12 (2H, m), 7.45 (1H, t, J = 8.7 Hz)
and 7.51 (1H, s, NH); LC/MS (ESI) m/z 339 (MÀH)+; HRMS (ESI)
calcd for C21H29N2O2 (M+H)+ 341.2229, found: 341.2211; HPLC tR
4.8 min (99%).
4.4.9. N-(Furan-2-ylmethyl)adamantane-1-carboxamide (14)
A white solid was obtained in 78% yield. mp 69–72 °C; 1H NMR
(CDCl3) d 1.65–1.75 (6H, m), 1.85 (6H, d, J = 2.8 Hz), 2.03 (3H, br),
4.41 (2H, d, J = 5.8 Hz), 5.85 (1H, br, NH), 6.19 (1H, d, J = 2.8 Hz),
6.30 (1H, dd, J = 3.3, 2.0 Hz) and 7.34 (1H,d, J = 1.9 Hz); LC/MS
(APCI) m/z 258 (M-H)+; HRMS (ESI) calcd for C16H22NO2 (M+H)+
260.1651, found: 260.1667; HPLC tR 2.6 min (99%).
4.4.17. N-Methyl-N-(4-methylbenzyl)adam-antane-1-
carboxamide (22)
A white solid was obtained in 87% yield. mp 93–95 °C; 1H NMR
(CDCl3) d 1.70 (6H, s, 3 Â CH2), 2.04 (9H, s), 2.32 (3H, s), 2.93 (3H,
s), 4.65 (2H, s) and 7.10 (4H, AB); LC/MS (ESI) m/z 298 (M+H)+;
HRMS (ESI) calcd for
C
20H28NO (M+H)+ 298.2171, found:
4.4.10. N-Methyl-N-((1-methyl-1H-pyrrol-2-yl)-
methyl)adamantane-1-carboxamide (15)
298.2189; HPLC tR 5.9 min (99%).
A white solid was obtained in 87% yield. mp 104–105.5 °C; 1H
NMR (CDCl3) d 1.76 (6H, s), 2.02 (9H, s), 3.02 (3H, s), 3.50 (3H, s),
4.61 (2H, s), 6.03 (2H, d, J = 2.3 Hz) and 6.58 (1H, t, J = 2.2 Hz);
LC/MS (APCI) m/z 287 (M+H)+; HRMS (ESI) calcd for C18H27N2O
(M+H)+ 287.2123, found: 287.2108; HPLC tR 6.6 min (99%).
4.4.18. N-(4-Chlorobenzyl)-N-methyladam-antane-1-
carboxamide (23)
A white solid was obtained in 54% yield. mp 65–66.5 °C; 1H
NMR (CDCl3) d 1.71 (6H, s), 2.03 (9H, s), 2.98 (3H, s3), 4.61 (2H,
s) and 7.20 (4H, AB); LC/MS (ESI) m/z 318 (M+H)+; HRMS (ESI) calcd
for
C
19H25ClNO (M+H)+ 318.1625, found: 318.1615; HPLC tR
4.4.11. N-((1-Methyl-1H-pyrrol-2-yl)meth-yl)-adamantane-1-
carboxamide (16)
6.2 min (99%).
A white solid was obtained in 76% yield. mp 117–119 °C; 1H
NMR (CDCl3) d 1.58–1.75 (6H, m), 1.83 (6H, d, J = 2.8 Hz), 2.02
(3H, br s), 3.53 (3H, s), 4.42 (2H, d, J = 5.2 Hz), 5.60 (1H, br, NH),
6.05 (2H, d, J = 2.2 Hz) and 6.65 (1H,t, J = 2.2 Hz); LC/MS (APCI)
m/z 271 (MÀH)+; HRMS (ESI) calcd for C17H24N2NaO (M+Na)+
295.1786, found 295.1768; HPLC tR 2.7 min (99%).
4.4.19. N-Methyl-N-(pyridin-3-ylmethyl)-adamantane-1-
carboxamide (24)
A white solid was obtained in 91% yield. mp 57–59.5 °C; 1H
NMR (CDCl3) d 1.70 (6H, s), 2.03 (9H, s), 3.05 (3H, s), 4.62 (2H, s),
7.25 (1H, dd, J = 7.9, 5.0 Hz), 7.53 (1H, dt, J = 7.9, 1.7 Hz), 8.46
(1H, d, J = 1.7 Hz) and 8.50 (1H, dd, J = 4.9, 1.5 Hz); LC/MS (ESI)
m/z 285 (M+H)+; HRMS (ESI) calcd for C18H25N2O (M+H)+
285.1967, found: 285.1963; HPLC tR 5.5 min (99%).
4.4.12. N-Methyl-N-((1-methyl-1H-imidazol-2-
yl)methyl)adamantane-1-carboxamide (17)
A white solid was obtained in 50% yield. mp 175–176 °C; 1H
NMR (CDCl3) d 1.65–1.83 (6H, m), 1.98 (6H, d, J = 2.7 Hz), 2.03
(3H, br s), 3.33 (3H, s), 3.76 (3H, s), 4.82 (2H, s), 6.88 (1H, d,
J = 1.9 Hz) and 7.14 (1H, d, J = 1.9 Hz); LC/MS (ESI) m/z 310
(M+Na)+; HRMS (ESI) calcd for C17H26N3O (M+H)+ 288.2076, found
288.2079; HPLC tR 6.6 min (99%).
4.4.20. N-(Pyridin-3-ylmethyl)adamantane-1-carboxamide (25)
A white solid was obtained in 76% yield. mp 79–81.5 °C; 1H
NMR (CDCl3) d 1.64–1.78 (6H, m), 1.86 (6H, d, J = 2.8 Hz), 2.04
(3H, br s), 4.44 (2H, d, J = 6.0 Hz), 5.94 (1H, br, NH), 7.24 (1H, m),
7.58 (1H, dt, J = 8.0, 1.7 Hz) and 8.52 (2H, m); LC/MS (ESI) m/z
269 (MÀH)+; HRMS (ESI) calcd for C17H23N2O (M+H)+ 271.1810,
found: 271.1816; HPLC tR 2,3 min (99%).
4.4.13. N-Methyl-N-((1-methyl-1H-pyrazol-5-yl)-
methyl)adamantane-1-carboxamide (18)
A white solid was obtained in 90% yield. mp 102–103.5 °C; 1H
NMR (CDCl3) d 1.71 (6H, s), 2.01 (9H, s), 3.10 (3H, s), 3.70 (3H, s),
4.58 (2H, s) and 5.87 (1H, s); LC/MS (ESI) m/z 288 (M+H)+; HRMS
(ESI) calcd for C17H26N3O (M+H)+ 288.2076, found: 288.2068; HPLC
tR 5.3 min (99%).
4.4.21. N-(Pyridin-2-ylmethyl)adamantane-1-carboxamide (26)
A white solid was obtained in 70% yield. mp 91–93.5 °C; 1H
NMR (CDCl3) d 1.70 (6H, m), 1.91 (6H, d, J = 3.0 Hz), 2.05 (3H, br
s), 4.52 (2H, d, J = 4.7 Hz), 6.95 (1H, br, NH), 7.15–7.24 (2H, m),
7.64 (1H, td, J = 7.9, 2.0 Hz) and 8.53 (1H, d, J = 4.5 Hz); LC/MS
(ESI) m/z 269 (M-H)+; HRMS (ESI) calcd for C17H23N2O (M+H)+
271.1810, found: 271.1813; HPLC tR 2,5 min (99%).
4.4.14. N-Methyl-N-((4-methylthiazol-2-yl)-
methyl)adamantane-1-carboxamide (19)
A colourless thick oil was obtained in 88% yield. 1H NMR (CDCl3)
d 1.71 (6H, s), 2.03 (9H, s), 2.41 (3H, s), 3.19 (3H, s), 4.80 (2H, s) and
6.81 (1H, s); LC/MS (ESI) m/z 305 (M+H)+; HRMS (ESI) calcd for
4.4.22. N-Methyl-N-((6-methylpyridin-2-yl)-
methyl)adamantane-1-carboxamide (27)
C
17H25N2OS (M+H)+ 305.1688, found: 305.1672; HPLC tR 6.0 min
A white solid was obtained in 80% yield. mp 76–77.5 °C; 1H
NMR (CDCl3) d 1.69 (6H, s), 2.03 (9H, s), 2.53 (3H, s), 3.06 (3H, s),
4.76 (2H, s), 6.91 (1H, d, J = 7.6 Hz), 7.02 (1H, d, J = 7.6 Hz) and
7.53 (1H, t, J = 7.7 Hz); LC/MS (ESI) m/z m/z 299 (M+H)+; HRMS
(ESI) calcd for C19H27N2O (M+H)+ 299.2123, found: 299.2121; HPLC
tR 6.0 min (99%).
(99%).
4.4.15. N-(3-Aminobenzyl)-N-methyladam-antane-1-
carboxamide (20)
An off-white solid was obtained in 88% yield. mp 105–106.5 °C;
1H NMR (CDCl3) d 1.70 (6H, s), 2.04 (9H, s), 2.94 (3H, s), 3.65 (2H, s,
NH2), 4.60 (2H, s), 6.49 (1H, br), 6.54-6.59 (2H, m) and 7.09 (1H, t,
J = 7.6 Hz); LC/MS (ESI) m/z 299 (M+H)+; HRMS (ESI) calcd for
C19H27N2O (M+H)+ 299.2123, found: 299.2117; HPLC tR 2.3 min
(99%).
4.4.23. N-Methyl-N-(2-(pyridin-2-yl)ethyl)-adamantane-1-
carboxamide (30)
A white solid was obtained in 83% yield. mp 64–65 °C; 1H NMR
(CDCl3) d 1.69 (6H, s), 1.91–2.01 (9H, m), 3.01 (2H, t, J = 7.3 Hz),
3.04 (3H, s, NCH3), 3.73 (2H, t, J = 7.1 Hz), 7.10–7.25 (2H, m), 7.59
(1H, td, J = 7.7, 2.0 Hz), and 8.53 (1H, dq, J = 4.7, 0.8 Hz); LC/MS
(ESI) m/z 299 (M+H)+; HRMS (ESI) calcd for C19H27N2O (M+H)+
299.2123, found 299.2116; HPLC tR 3.6 min (99%).
4.4.16. N-(3-Acetamidobenzyl)-N-methyl-adamantane-1-
carboxamide (21)
A white solid was obtained in 55% yield. mp 109–111 °C; 1H
NMR (CDCl3) d 1.70 (6H, s), 2.03 (9H, s), 2.16 (3H, s), 2.95 (3H, s),

X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
6401
4.4.24. N-(2-(Pyridin-2-yl)ethyl)adamant-ane-1-carboxamide
(31)
A white solid was obtained in 88% yield. mp 76–79 °C; 1H NMR
4.4.31. 2-(Adamantan-1-yl)-N-methyl-N-(pyridin-3-
ylmethyl)acetamide (37)
An off-white solid was obtained in 52% yield. mp 67–68.5 °C; 1H
NMR (CDCl3) d 1.58–1.72 (12H, m), 1.96 (3H, br), 2.19 (2H, s), 2.97
(3H,), 4.60 (2H, s), 7.24 (1H, m), 7.65 (1H, dt, J = 8.2, 1.7 Hz) and
8.47-8.57 (2H, m); LC/MS (ESI) m/z 299 (M+H)+; HRMS (ESI) calcd
for C19H27N2O (M+H)+ 299.2123, found: 299.2130; HPLC tR 2.1 min
(98%).
(CDCl3) d 1.62–1.72 (6H, m), 1.78 (6H, d, J = 2.6 Hz), 2.00 (3H, br s),
2.98 (2H, t, J = 6.4 Hz), 3.60 (2H, q, J = 6.4 Hz), 6.70 (1H, br, NH),
7.10–7.18 (2H, m), 7.62 (1H, td, J = 7.9, 1.7 Hz) and 8.52 (1H, d,
J = 4.4 Hz). LC/MS (ESI) m/z 285 (M+H)+; HRMS (ESI) calcd for
C
18H25N2O (M+H)+ 285.1967, found: 285.1977; HPLC tR 2.5 min
(99%).
4.4.32. 2-(Adamantan-1-yl)-N-(pyridin-2-yl-methyl)acetamide
(38)
4.4.25. N-(2-(Pyridin-3-yl)ethyl)adamant-ane-1-carboxamide
(32)
A white solid was obtained in 86% yield. mp 87–88.5 °C; 1H
NMR (CDCl3) d 1.58–1.70 (12H, m), 1.95 (3H, br s), 2.02 (2H, s),
4.54 (2H, d, J = 4.9 Hz), 6.60 (1H, br, NH), 7.16–7.29 (2H, m), 7.65
(1H, td, J = 7.7, 2.0 Hz) and 8.52 (1H, d, J = 5.0 Hz); LC/MS (ESI) m/
z 285 (M+H)+; HRMS (ESI) calcd for C18H25N2O (M+H)+ 285.1967,
found: 285.1962; HPLC tR 2.5 min (99%).
A white solid was obtained in 72% yield. mp 83–85 °C; 1H NMR
(CDCl3) d 1.02–1.12 (12H, m), 1.34 (3H, br s), 2.16 (2H, t, J = 6.2 Hz),
2.82 (2H, q, J = 6.2 Hz), 4.95 (1H, br, NH), 6.58 (1H, m), 6.85 (1H, m)
and 7.82 (2H, m); LC/MS (ESI) m/z 283 (MÀH)+; HRMS (ESI) calcd
for C18H25N2O (M+H)+ 285.1967, found: 285.1968; HPLC tR
2.5 min (99%).
4.4.33. N-Methyl-N-(thiophen-2-ylmethyl)-
4.4.26. 2-(Adamantan-1-yl)-N-methyl-N-(thiophen-2-
ylmethyl)acetamide (4)
tRicyclo[3.3.1.0(3,7)]nonane-3- carboxamide (39)
A colourless oil was obtained in 86% yield. mp 87–88.5 °C; 1H
NMR (CDCl3) d 1.59–1.68 (4H, m), 1.87–1.95 (4H, m), 2.10–2.15
(2H, m), 2.32 (2H, br s), 2.91 (1H, bt, J = 6.6 Hz), 3.02 (3H, br s,
NCH3), 4.74 (2H, s), 6.95 (2H, m, J = 3.4 Hz) and 7.21–7.25 (1H,
m); LC/MS (ESI) m/z 276 (M+H)+; HRMS (ESI) calcd for C16H22NOS
(M+H)+ 276.1422, found: 276.1425; HPLC tR 2.8 min (97%).
A white solid was obtained in 68% yield. mp 107–109 °C; 1H
NMR (CDCl3) d 1.62–1.77 (12H, m), 2.00 (3H, br s), 2.19 (2H, s),
3.00 (3H, s), 4.52 (2H, s), 6.95 (2H, m) and 7.23 (1H, dd, J = 5.0,
1.3 Hz); LC/MS (ESI) m/z 304 (M+H)+; HRMS (ESI) calcd for
C
18H26NOS (M+H)+ 304.1735, found 304.1726; HPLC tR 3.8 min
(99%).
4.4.34. N,1-Dimethyl-N-(thiophen-2-
4.4.27. 2-(Adamantan-1-yl)-N-(thiophen-2-ylmeth-
yl)acetamide (33)
ylmethyl)cyclohexanecarboxamide (40)
A clear oil was obtained in 83% yield. 1H NMR (CDCl3) d 1.25
(3H, s), 1.31–1.41 (3H, m), 1.47–1.58 (5H, m), 2.10–2.16 (2H, m),
3.06 (3H, s), 4.73 (2H, s), 6.94–6.96 (2H, m), 7.22–7.24 (1H, m);
LC/MS (ESI) m/z 252 (M+H)+; HRMS (ESI) calcd for C14H22NOS
(M+H)+ 252.1422, found: 252.1421; HPLC tR 2.7 min (99%).
A white solid was obtained in 62% yield. mp 117–119 °C; 1H
NMR (CDCl3) d 1.56–1.71 (12H, m), 1.93 (2H, s), 1.95 (3H, br s),
4.60 (2H, d, J = 5.2 Hz), 5.63 (1H, br, NH), 6.90–6.95 (2H, m) and
7.21 (1H, dd, J = 4.7, 1.5 Hz); LC/MS (ESI) m/z 288 (MÀH)+; HRMS
(ESI) calcd for C17H24NOS (M+H)+ 290.1579, found 290.1585; HPLC
tR 2.8 min (99%).
4.4.35. N-Methyl-N-(thiophen-2-ylmethyl)-1-p-
tolylcyclopropanecarboxamide (41)
4.4.28. 2-(Adamantan-1-yl)-N-methyl-N-(thio-phen-3-
ylmethyl)acetamide (34)
A clear oil was obtained in 53% yield. 1H NMR (CDCl3) d 1.15
(2H, br s), 1.41 (2H, br s), 2.29 (3H, s), 2.80 (3H, s), 4.70 (2H, s),
6.91 (1H, s) and 7.05–7.26 (6H, m); LC/MS (ESI) m/z 308
(M+Na)+; HRMS (ESI) calcd for C17H20NOS (M+H)+ 286.1266, found
286.1246; HPLC tR 2.3 min (99%).
A white solid was obtained in 62% yield. mp 117–119 °C; 1H
NMR (CDCl3) signals from rotamers in 2:1 ratio: d 1.55–1.75
(12H, m), 1.95 (3H, br), 2.16 (2H, s), 2.95 (3H, s), 4.57 (2H, s),
7.02 (1H, m), 7.11 (1H, m) and 7.26 (1H, m); d 1.55–1.75 (12H,
m), 1.95 (3H, br), 2.19 (2H, s), 2.92 (3H, s), 4.54 (2H, s), 6.91 (1H,
m), 7.02 (1H, m) and 7.33 (1H, m); LC/MS (ESI) m/z 304 (M+H)+;
4.4.36. 1-(4-Chlorophenyl)-N-methyl-N-(thio-phen-2-ylmethyl)
cyclopropanecarbox-amide (42)
HRMS (ESI) calcd for
C
18H26NOS (M+H)+ 304.1735, found
A clear oil was obtained in 72% yield. 1H NMR (CDCl3) d 1.15
(2H, br s), 1.45 (2H, br s), 2.79 (3H, s), 4.70 (2H, s), 7.02 (1H, s),
7.07 (2H, br s), and 7.21–7.24 (4H, m); LC/MS (ESI) m/z 328
(M+Na)+; HRMS (ESI) calcd for C16H17ClNOS (M+H)+ 306.0719,
found: 306.0707; HPLC tR 2.3 min (99%).
304.1718; HPLC tR 2.9 min (99%).
4.4.29. 2-(Adamantan-1-yl)-N-methyl-N-[(1-methyl-1H-pyrrol-
2-yl)methyl]acetamide (35)
A white solid was obtained in 50% yield. mp 75–76.5 °C; 1H
NMR (CDCl3) d 1.60–1.72 (12H, m), 1.95 (3H, br), 2.14 (2H, s),
2.88 (3H, s), 3.57 (3H, s), 4.59 (2H, s), 6.03–6.07 (2H, m) and 6.59
(1H, t, J = 2.1 Hz); LC/MS (ESI) m/z 323 (M+Na)+; HRMS (ESI) calcd
for C19H29N2O (M+H)+ 301.2280, found: 301.2272; HPLC tR 2.8 min
(98%).
4.4.37. 1-(4-Chlorophenyl)-N-methyl-N-(thio-phen-2-
ylmethyl)cyclobutanecarbox-amide (43)
A clear oil was obtained in 49% yield. 1H NMR (CDCl3) d 1.95
(2H, m), 2.34 (2H, t, J = 9.5 Hz), 2.47 (3H, s), 2.86 (2H, t,
J = 10 Hz), 4.68 (2H, s), 6.89 (2H, br s) and 7.20–7.31 (5H, m); LC/
MS (ESI) m/z 342 (M+Na)+; HRMS (ESI) calcd for C17H19ClNOS
(M+H)+ 320.0876, found: 320.0861; HPLC tR 2.7 min (99%).
4.4.30. 2-(Adamantan-1-yl)-N-[(1-methyl-1H-pyrrol-2-
yl)methyl]acetamide (36)
A white solid was obtained in 50% yield. mp 92–95 °C; 1H NMR
(CDCl3) d 1.55 (6H, d, J = 2.8 Hz), 1.57–1.62 (6H, m), 1.85 (2H, s),
1.91 (3H, br), 3.51 (3H, s), 4.35 (2H, d, J = 5.2 Hz), 5.30 (1H, br,
NH), 6.00(2H, d, J = 2.3 Hz) and 6.55 (1H, t, J = 2.2 Hz); LC/MS
(ESI) m/z 285 (MÀH)+; HRMS (ESI) calcd for C18H27N2O (M+H)+
287.2123, found: 287.2112; HPLC tR 2.9 min (99%).
4.4.38. 1-(4-Chlorophenyl)-N-methyl-N-(thio-phen-2-
ylmethyl)cyclopentanecarbox-amide (44)
A white solid was obtained in 88% yield. mp 58–60 °C; 1H NMR
(CDCl3) d 1.62–1.82 (4H, m), 1.93–2.10 (3H, m), 2.43–2.52 (1H, m),
2.53 (3H, br s), 4.69 (2H, br s), 6.92 (2H, d, J = 3.0 Hz), 7.12-7.24
(5H, m); LC/MS (ESI) m/z 334 (M+H)+; HRMS (ESI) calcd for

6402
X. Su et al. / Bioorg. Med. Chem. 20 (2012) 6394–6402
C18H21ClNOS (M+H)+ 334.1032, found: 334.1029; HPLC tR 3.1 min
(99%).
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Acknowledgments
This work was supported by Sterix Ltd, a member of the Ipsen
Group, and by the Wellcome Trust (Programme Grant 082837
and VIP funding). We thank Ms. A. Smith for technical assistance,
N. Muller and I. Viossat for CYP inhibition and metabolic stability
studies. We also thank the EPSRC National Mass Spectrometry
Service Centre at the University of Wales, Swansea for some high
resolution accurate mass measurements.
24. Su, X.; Pradaux-Caggiano, F.; Thomas, M. P.; Szeto, M. W.; Halem, H. A.; Culler,
M. D.; Vicker, N.; Potter, B. V. L. ChemMedChem 2010, 5, 1026.
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