Adamantyl ethanone pyridyl derivatives: Potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1

Article abstract of DOI:10.1002/cmdc.201100182

Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type2 diabetes and obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11β-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective for this isoform, with no activity against 11β-HSD2 and 17β-HSD1. Structure-activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC₅₀ values around 34-48nM against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.

Full text of DOI:10.1002/cmdc.201100182

MED
DOI: 10.1002/cmdc.201100182
Adamantyl Ethanone Pyridyl Derivatives: Potent and
Selective Inhibitors of Human 11b-Hydroxysteroid
Dehydrogenase Type 1
Xiangdong Su,[a] Fabienne Pradaux-Caggiano,[a] Nigel Vicker,[a] Mark P. Thomas,[a]
Heather Halem,[b] Michael D. Culler,[b] and Barry V. L. Potter*[a]
Elevated levels of active glucocorticoids have been implicated
in the development of several phenotypes of metabolic syn-
drome, such as type 2 diabetes and obesity. 11b-Hydroxyste-
roid dehydrogenase type 1 (11b-HSD1) catalyses the intracellu-
lar conversion of inactive cortisone to cortisol. Selective 11b-
HSD1 inhibitors have shown beneficial effects in various condi-
tions, including diabetes, dyslipidemia and obesity. A series of
adamantyl ethanone pyridyl derivatives has been identified,
providing potent and selective inhibitors of human 11b-HSD1.
Lead compounds display low nanomolar inhibition against
human and mouse 11b-HSD1 and are selective for this isoform,
with no activity against 11b-HSD2 and 17b-HSD1. Structure–ac-
tivity relationship studies reveal that an unsubstituted pyridine
tethered to an adamantyl ethanone motif through an ether or
sulfoxide linker provides a suitable pharmacophore for activity.
The most potent inhibitors have IC50 values around 34–48 nm
against human 11b-HSD1, display reasonable metabolic stabili-
ty in human liver microsomes, and weak inhibition of key
human CYP450 enzymes.
Introduction
Metabolic syndrome refers to a cluster of metabolic disorders,
including insulin resistance, hyperglycemia, visceral obesity, hy-
pertension and dyslipidemia. Combinations of these conditions
represent major risk factors for developing cardiovascular dis-
ease and type 2 diabetes.[1,2] The rapid increase in the preva-
lence of cardiovascular disease and type 2 diabetes demands
novel and effective approaches for the prevention and treat-
ment of the syndrome. Previous studies have implicated exces-
sive glucocorticoid action in the development of several phe-
notypes associated with metabolic syndrome.[3–5] Abnormal
glucocorticoid receptor (GR) signalling is associated with insu-
lin and leptin resistance, leading to the development of type 2
diabetes, obesity and cardiovascular disorders.[6,7] GR activation
stimulates hepatic glucose production, antagonises insulin se-
cretion from pancreatic b-cells and insulin-mediated glucose
uptake in peripheral tissues,[8–11] and it also promotes lipolysis
and fatty acid mobilisation.[12]
disorders. The intracellular metabolism of glucocorticoid is
mediated by 11b-hydroxysteroid dehydrogenase isozymes
(11b-HSDs), which are microsomal enzymes from the short-
chain dehydrogenase/reductase family. The 11b-hydroxysteroid
dehydrogenase type 1 (11b-HSD1), highly expressed in liver,
adipose tissue and the central nervous system, acts as an
NADPH-dependent reductase, converting cortisone in humans
to the active glucocorticoid cortisol. The prereceptor activation
of cortisone mediated by 11b-HSD1 provides a mechanism for
specific tissues to produce intracellular, nonadrenal cortisol,
thereby locally amplifying the glucocorticoid action.[18] Con-
versely, the 11b-HSD2 isoform is exclusively NAD+ dependent
and mainly expressed in mineralocorticoid target tissues, such
as the cortical collection ducts of the kidney and the distal
colon. 11b-HSD2 catalyses the transformation of cortisol to in-
active cortisone and reduces the local concentration of cortisol
in specific tissues. This mechanism prevents activation of the
by cortisol in renal cortical collecting ducts and distal colon.
Reduced 11b-HSD2 function may result in sodium retention,
hypokalemia and hypertension.[19–21]
Metabolic syndrome shares similar characteristics with symp-
toms of Cushing’s syndrome, a systemic glucocorticoid excess
condition.[13] As the metabolic abnormalities in Cushing’s syn-
drome can be improved to a certain degree by reducing the
excessive glucocorticoid action,[14–16] the similarities between
phenotypes of metabolic syndrome and Cushing’s syndrome
suggest the possibility of treating the individual indications of
metabolic syndrome by glucocorticoid activity suppression.
Systemic glucocorticoid levels are generally normal in pa-
tients with common forms of obesity or overweight type 2 dia-
betics.[17] Since GR signalling depends not only on the circulat-
ing glucocorticoid level, but also on the prereceptor activation
of glucocorticoid within cells, it is speculated that the intracel-
lular glucocorticoid concentration is responsible for metabolic
[a] Dr. X. Su, Dr. F. Pradaux-Caggiano, Dr. N. Vicker, Dr. M. P. Thomas,
Prof. B. V. L. Potter
Medicinal Chemistry, Department of Pharmacy and Pharmacology
University of Bath, Bath, BA2 7AY (UK)
Fax: (+44)1225 386114
E-mail: B.V.L.Potter@bath.ac.uk
[b] Dr. H. Halem, Dr. M. D. Culler
IPSEN, Biomeasure Inc., 27 Maple Street, Milford, MA 01757 (USA)
Re-use of this article is permitted in accordance with the Terms and Con-
ditions set out at http://onlinelibrary.wiley.com/journal/
10.1002/(ISSN)1860-7187/homepage/2452_onlineopen.html.
1616
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
The correlation between 11b-HSD1 activity, obesity and dia-
betes has also been validated with genetically modified rodent
models. Transgenic mice with fat-tissue-specific overexpression
of 11b-HSD1 develop symptoms of insulin-resistant diabetes,
hyperlipidemia and visceral obesity.[22,23] In contrast, studies
with 11b-HSD1 knock-out mice demonstrate that these animals
resist stress-induced hyperglycaemia, diet-induced obesity, and
have decreased cholesterol and triglyceride levels.[24,25] Similar-
ly, specific overexpression of 11b-HSD2 in adipose tissue in
transgenic mice also results in increased insulin sensitivity, glu-
cose tolerance, and resistance to body weight gain on a high-
fat diet.[26] 11b-HSD1 activity suppression in animal models
with selective inhibitors was found to provide beneficial effects
in various indications of metabolic syndrome.[27–29] Moreover,
clinical studies suggest that inhibition of 11b-HSD1 with carbe-
noxolone, a nonselective inhibitor, increases hepatic insulin
sensitivity and decreases glucose production.[30,31]
when examined in a HEK293 cell line stably transfected with
the HSD11B1 gene (Figure 1). These compounds also show rea-
sonable metabolic stability when incubated with human liver
microsomes. To improve potency, pharmacokinetic properties
and physicochemical properties, we performed further optimi-
sation on this series of compound using structure-based
design.[43] We synthesised compounds containing a pyridyl ring
tethered to an adamantyl ethanone motif through an oxygen,
sulfur, sulfoxide, sulfone or amide linker, and examined their in-
hibitory activity against human 11b-HSD1. Selected potent
compounds were also tested for activity against mouse 11b-
HSD1. Their selectivity for 11b-HSD1 over 11b-HSD2 and 17b-
HSD1 was also examined.
Results and Discussion
Chemistry
The concept of treating type 2 diabetes, obesity, and other
metabolic abnormalities through selective inhibition of 11b-
HSD1 activity with small-molecule inhibitors has attracted con-
siderable interest in the pharmaceutical industry over the last
Adamantyl ethanones 6–12, with an oxygen linker, were pre-
pared by a nucleophilic coupling reaction between the corre-
sponding pyridinol and 1-adamantyl bromomethyl ketone (5)
under basic conditions (Scheme 1). Compound 5 was reacted
with commercially available pyridine thiol using triethylamine
in acetonitrile to give the corresponding sulfur linker com-
pounds (13–15, 22 and 23). Further oxidation of these com-
pounds with meta-chloroperbenzoic acid (m-CPBA) at low tem-
Figure 1. Known potent inhibitors of 11b-HSD1. The inhibitory activities of
compounds 1–4 were measured in HEK293 cells transfected with the human
HSD11B1 gene.[38, 41–42]
Scheme 1. Synthesis of the adamantyl ethanone compounds (for Ar, see
Tables 1–3). Reagents and conditions: a) ArOH, K2CO3, acetone, RT; b) ArSH,
Et3N, CH3CN, RT; c) m-CPBA, CH2Cl2, ꢀ10!08C.
decade.[32–36] Newly discovered potent and selective 11b-HSD1
inhibitors have been extensively reviewed.[32–37] PF915275 (1;
Figure 1), an inhibitor developed by Pfizer, has shown modest
11b-HSD1 inhibition in a clinical study.[38] Results from a posi-
tive proof-of-concept clinical study of 11b-HSD1 inhibitor
INCB013739, developed by Incyte, provide substantial evidence
that inhibition of 11b-HSD1 can be a viable treatment of
type 2 diabetes. INCB013739 treatment of type 2 diabetes mel-
litus patients who failed on metformin monotherapy show sig-
nificantly improved hepatic and peripheral insulin sensitivity
and reduced haemoglobin A1c and fasting plasma glucose
levels. In patients with hyperlipidaemia or hypertriglyceridae-
mia, treatment with INCB013739 also lowers triglyceride and
cholesterol levels.[39,40]
perature generates in one step both sulfoxide (16–18) and sul-
fone (19–21), which can be separated using flash chromatogra-
phy (Scheme 1).
Starting from 23, the pyridyl carboxamide derivatives 24–27
were synthesised with amide formation reactions using 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and 4-di-
methylaminopyridine (DMAP) as catalysts (Scheme 2).
The extended ether linker compounds 28–34 were synthes-
ised from compound 5 and the corresponding pyridyl methyl
alcohol under basic conditions using sodium hydride in a tetra-
hydrofuran (THF) solution (Scheme 3). Compounds 28 and 31
were transformed into their oxime derivatives 35 and 36, re-
spectively, as illustrated in Scheme 3. The target compounds
with an extended sulfur linker were prepared by two different
We previously identified some adamantyl ethanone deriva-
tives as potent inhibitors of human 11b-HSD1.[41,42] Compounds
2–4 exhibit high inhibitory activity with nanomolar IC50 values
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1617

B. V. L. Potter et al.
MED
Scheme 5. Synthesis of amide linker compounds 56–61 (for R, see Table 7).
Reagents and conditions: a) H2, 5% Pd/C, CH3OH, 36% HCl, RT, 6 h, 95%;
b) RCOOH, EDCI, DMAP, Et3N, CH2Cl2, RT, overnight.
Scheme 2. Synthesis of pyridyl carboxamide derivatives 24–27. Reagents and
conditions: a) EDCI, DMAP, Et3N, CH2Cl2, corresponding amine, RT, overnight.
Hydrogenation of 54 under acidic conditions gave amine inter-
mediate 55, which was reacted with the corresponding carbox-
ylic acid to generate the target compounds 56–61 (Scheme 5).
Structure–activity relationships
We previously identified potent and selective 11b-HSD1 inhibi-
tors from compounds with an adamantyl ethanone core struc-
ture. Lead compounds 2–4, with a substituted phenyl ring or
5-membered aromatic heterocycle tethered to the adamantyl
ethanone moiety through an oxygen or sulfur linker, display
selective inhibitory activity against both human and mouse
11b-HSD1.[41] To further optimise this series of 11b-HSD1 inhibi-
tors, we designed and synthesised novel compounds based on
the same core structure but with a pyridyl ring attached to the
ethanone motif. The target compounds were tested for their
inhibition against 11b-HSD1 in a HEK293 cell line transfected
with the HSD11B1 gene. As inhibitory activity was tested in
intact cells, the result represents the cumulative effects of a
compound’s cellular transportation, metabolism and binding
affinity to 11b-HSD1.
Scheme 3. Synthesis of compounds with an extended linker (for Ar, see
Tables 4 and 5). Reagents and conditions: a) ArCH2OH, NaH, THF, 08C;
b) NH2OH·HCl, Et3N, EtOH, reflux, overnight; c) 1. ArCH2SC(NH)NH2·2HCl,
NaOH, reflux; 2. Et3N, CH3CN, RT; d) m-CPBA, CH2Cl2, ꢀ10!08C.
routes. Chloromethylpyridine was reacted with thiourea in eth-
anol to make the corresponding pyridinylmethyl carbamimido-
thioate dihydrochloride; the intermediate was then hydrolysed
under basic conditions to generate the corresponding thiol,
which was then transformed in situ into compounds 37–39
through a nucleophilic substitution reaction with compound 5
(Scheme 3).
In the ethanone ether series, compound 6, with a 6-methyl-
2-pyridyl ring, exhibited only moderate activity (IC50 =3.1 mm).
Replacing the 6-methyl group with an electron-withdrawing
chloro or trifluoro group at either the 6- or 5-position resulted
in loss of activity (compounds 7, 8). However, the 6-methyl-3-
pyridyl compound 11 displays greatly enhanced activity with
an IC50 value of 81 nm, a 38-fold improvement compared with
the 2-pyridyl analogue 6, suggesting that the nitrogen position
is critical with such a linker system. More interestingly, the non-
substituted compound 12 shows even greater inhibition
(IC50 =27 nm), indicating that the methyl group hinders the
binding of the pyridyl nitrogen in the active site. This observa-
tion is in agreement to what was found in the 5-membered
heterocyclic series, suggesting limited steric and/or electronic
requirements around the aromatic ring (Table 1).
Compound 46, obtained by reacting 5 with potassium etha-
nethioate, was hydrolysed in basic conditions to produce the
intermediate 2-mercapto-1-adamantylethanone, which was re-
acted in situ with the corresponding chloromethylpyridine to
afford compounds 47–49 (Scheme 4). Sulfoxides 40–42, 50
and sulfones 43–45, 51–53 were obtained by m-CPBA oxida-
tion of their corresponding thioether compound.
The target compounds with an amide linker were prepared
from the azido ethanone 54, which was obtained through a
nucleophilic substitution of compound 5 with sodium azide.
Replacing the oxygen linker with a sulfur atom in the same
core structure generates some highly potent inhibitors. Both 2-
pyridyl (13) and 4-pyridyl (15) derivatives display high potency
with IC50 values of ~60 nm (Table 2). However, the 6-methyl
substituent has a negative effect on the activity, as compound
14 shows only 70% inhibition at 1 mm. Interestingly, the corre-
sponding sulfoxide linker derivatives 16–18 are all highly
active. The 2-pyridyl compound 16 (IC50 =33 nm) doubles the
potency when compared with the sulfide linker analogue 13,
whereas 4-pyridyl derivative 18 (IC50 =15 nm) displays a four-
fold increase in inhibitory activity and is one of the most
Scheme 4. Synthesis of substituted pyridyl derivatives 47–53 (for Ar, see
Table 6). Reagents and conditions: a) 1. 1n NaOH, acetone, RT; 2. ArCH2Cl,
Et3N, CH3CN, RT; b) m-CPBA, CH2Cl2, ꢀ10!08C.
1618
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
Table 1. Cellular 11b-HSD1 inhibition by compounds 6–12.
Table 2. Cellular 11b-HSD1 inhibition by compounds 13–21.
Compd
Ar[a]
IC50[b] [nm]
Compd
X
S
Ar[a]
IC50[b] [nm]
13
66
6
3109
14
S
70%[c]
7
28%[c]
15
16
S
62
33
8
9
40%[c]
30%[c]
SO
17
SO
24
10
11
12
1362
81
18
19
SO
15
SO2
211
27
20
21
SO2
SO2
375
83
[a] Indicates point of attachment. [b] IC50 values are reported as the
*
mean value of three measurements with variance less than 20%. [c] Per-
cent inhibition measured at 1 mm and reported as the mean value of two
measurements.
[a] Indicates point of attachment. [b] IC50 values are reported as the
*
mean value of three measurements with variance less than 20%. [c] Per-
cent inhibition measured at 1 mm and reported as the mean value of two
measurements.
potent compounds in this series. Even the 6-methyl-substitut-
ed compound 17 retains the activity with an IC50 value of
24 nm. The trend of a sulfoxide linker compound normally ex-
hibiting better activity than the corresponding sulfide ana-
logue was also observed in our previous studies,[41,42] suggest-
ing the possibility of the oxygen on the sulfur forming added
interactions with the protein or altering the geometry of the
molecule placing the adamantyl and/or the aromatic ring in a
preferred position for binding in the active site. Surprisingly, a
detrimental effect was found when the sulfoxide was replaced
with a sulfone group. Compounds 19–21 lose about 6–15-fold
activity compared with their sulfoxide linker counterparts, indi-
cating that the extra oxygen is not favoured for inhibition with
such a structural combination and geometry.
Table 3. Cellular 11b-HSD1 inhibition by compounds 22–27.
Compd
R
IC50[a] [nm]
22
23
24
25
26
27
CF3
COOH
CONH2
CONHMe
CONHEt
CONMe2
3380
345
95
73%[b]
7302
80
Alteration of the substituent on the 2-pyridyl ring was ex-
plored to investigate if a hydrogen-bonding group on the aro-
matic ring may potentially improve inhibition (Table 3). The
substitution of a trifluoro group at the 5-position (22, IC50 =
3380 nm) results in a disastrous 51-fold reduction in activity
when compared with the unsubstituted derivative 13. The 5-
carboxylic acid substitution performs better than that of the
trifluoro group, but still gives a compound fivefold less active
(23, IC50 =345 nm) in comparison with 13. Converting the acid
to different carboxamide groups gives mixed results; while the
CONH2 or CONMe2 substitution generates compounds (24,
IC50 =95 nm; 27, IC50 =80 nm) at nearly the same level as un-
substituted 13, the CONHMe or CHNHEt substitution only
[a] IC50 values are reported as the mean value of three measurements
with variance less than 20%. [b] Percent inhibition measured at 1 mm and
reported as the mean value of two measurements.
gives compounds (25, 26) of poor activity. The results suggest
that the subtle change of a steric and/or electronic effect
around the aromatic ring may have a large impact on inhibito-
ry activity.
The ethanone ether linker was further extended with an
extra methylene unit to generate more flexible molecules
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1619

B. V. L. Potter et al.
MED
Table 4. Cellular 11b-HSD1 inhibition by compounds 28–34.
Table 5. Cellular 11b-HSD1 inhibition by compounds 37–45.
Compd
Ar[a]
IC50[b] [nm]
Compd
X
Ar[a]
IC50[b] [nm]
28
48
37
S
86
38
S
72
29
99
39
40
S
53
47
30
31
182
34
SO
41
SO
46
42
43
SO
26
34
32
112
SO2
33
34
296
44
45
SO2
SO2
91
34
33%[c]
[a] Indicates point of attachment. [b] IC50 values are reported as the
*
[a] Indicates point of attachment. [b] IC50 values are reported as the
*
mean value of three measurements with variance less than 20%.
mean value of three measurements with variance less than 20%. [c] Per-
cent inhibition measured at 1 mm and reported as the mean value of two
measurements.
teresting to note that sulfoxide linker analogues 40–42 regain
activity by nearly twofold, following the same structure–activi-
ty relationship we observed previously. The 4-pyridyl derivative
42, with an IC50 value of 26 nm, is the most potent compound
in this series. It is also worth noting that that sulfone ana-
logues 43–45 display high potency at nearly the same level as
the sulfoxide compounds, especially 2-pyridyl and 4-pyridyl
compounds (43, IC50 =34 nm; 45, IC50 =34 nm); this is unlike
the observation for pyridyl compounds with the short version
of ethanone sulfone linker, which show reduced activity com-
pared with the sulfoxide compounds (Table 2). It is assumed
that even for compounds with a sulfone group linker, the mo-
lecular flexibility gained from the extended linker makes the
adamantyl and/or aromatic moiety adapt to more preferred
positions in the binding site.
(Table 4). The 2-pyridyl derivative 28 shows an impressive activ-
ity with an IC50 value of 48 nm. The 6-methyl substituent
brings down the inhibition by twofold (29, IC50 =99 nm), pro-
viding evidence that changing the substitution on the aromat-
ic ring is not favoured. The 3-pyridyl derivative 31 (IC50 =
34 nm) displays the same level of activity as 28, suggesting
that the position of the nitrogen is not as restricted when
combined with a more flexible linker. Attempts to achieve
better activity with either the electron-donating methoxy
group or the electron-withdrawing trifluoro group substitution
were not successful, as compounds 30, 32–34 all suffer some
degree of potency loss when compared with nonsubstituted
derivatives 28 or 31 (Table 4). Although compound 32 with a
4-methoxy group has an IC50 value of 100 nm, it is still three-
fold less active than 31. To understand the importance of the
ketone group, compounds 28 and 31 were transformed into
their corresponding oxime analogues 35 and 36, respectively;
none of the oxime compound shows any significant inhibition
at 1 mm. Reducing the ketone to an alcohol also results in a
total loss of the activity (data not shown), suggesting that the
carbonyl group is highly preferred in such a core structure.
Converting the oxygen linker of 28 or 31 to a sulfur linker
leads to a compound twofold less active (37, IC50 =86 nm; 38,
IC50 =72 nm; Table 5). The 4-pyridyl compound 39 also exhibits
similar potency with an IC50 value of 53 nm. However, it is in-
The effect of a substituent on the pyridine motif was again
investigated for the compounds with an extended linker
(Table 6). The 5-methoxy-substituted compound 47 shows
moderate activity with an IC50 value of 510 nm. With an elec-
tron-withdrawing group at the 6-position, both compounds 48
and 49 are poor inhibitors. The only compound with an IC50
value ~100 nm is the sulfoxide linked 6-chloropyridyl derivative
50 (Table 6).
We also investigated the structure–activity relationship in
the ethanone amide linker series (Table 7). The 2-pyridyl car-
boxamide 56 gives moderate potency with an IC50 value of
278 nm. Adding a 6-methyl group brings no change to the ac-
1620
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
mouse enzyme at the same level as that of the human enzyme
with IC50 values below 50 nm in both cases, making them suit-
able candidates for further in vivo study in mouse models. On
the other hand, compounds 12, 40–42 and 45 all display sig-
nificantly reduced activity against the mouse enzyme with IC50
Table 6. Cellular 11b-HSD1 inhibition by compounds 47–53.
Compd
X
R
IC50[a] [nm]
Table 8. Comparison of cellular 11b-HSD1 inhibition of human and
47
48
49
50
51
52
53
S
S
S
SO
SO2
SO2
SO2
5-OMe
6-CF3
6-Cl
510
mouse enzymes.[a]
20%[b]
31%[b]
117
Compd
IC50 (human) [nm]
IC50 (mouse) [nm]
6-Cl
5-OMe
6-CF3
6-Cl
67%[b]
54%[b]
903
12
16
17
18
28
31
40
41
42
43
45
27
33
24
15
48
34
47
46
26
34
34
160
43
68
61
44
[a] IC50 values are reported as the mean value of three measurements
with variance less than 20%. [b] Percent inhibition measured at 1 mm and
reported as the mean value of two measurements.
28
248
148
191
35
150
Table 7. Cellular 11b-HSD1 inhibition by compounds 56–61.
[a] IC50 values are reported as the mean value of three measurements
with variance less than 20%.
values ranging from 150 to 250 nm. Although compounds 17
and 18 are three- to fourfold less active on the mouse enzyme,
they still retain relatively high potency against both species
(Table 8). The potent compounds selected for evaluation
against mouse 11b-HSD1 (Table 8) were also tested for their in-
hibition against human 11b-HSD2 and 17b-HSD1 (data not
shown). The results indicate that all these compounds are inac-
tive at a concentration of 10 mm, and therefore they are re-
garded as highly selective 11b-HSD1 inhibitors.
Compd
Ar[a]
IC50[b] [nm]
56
278
57
294
58
59
60
151
239
193
As adamantyl ethanone compounds are lipophilic in nature,
their solubility in the aqueous phase is rather limited, which
could cause formulation issues in in vivo studies. The pyridine
ring in the core structure of our potent compounds can be
transformed into a salt form with improved solubility. Com-
pound 31 was converted to its hydrochloride salt form (62),
61
217
which demonstrates enhanced water solubility (>4 mgmLꢀ1
)
[a] Indicates point of attachment. [b] IC50 values are reported as the
*
mean value of three measurements with variance less than 20%.
in a Na2HPO4 buffer solution with or without 5% N,N-dimethy-
lacetamide (DMA) as a cosolvent. Compound 62 displays an
IC50 value of 141 nm in the cellular assay against human 11b-
HSD1. The difference in activity between the parent compound
and its salt form may be due to the dissociation rate in the
assay buffer.
tivity (57, IC50 =294 nm); however, the 3-pyridyl derivative 58
(IC50 =151 nm) is about twofold more active than 28. Changing
to a para-substituted pyridyl (59, IC50 =239 nm) or inserting an
extra methylene unit between the pyridyl ring and the amide
group (60, IC50 =193 nm; 61, IC50 =217 nm) gave compounds
with only modest potency. Therefore, it is believed that the
amide linker is not a suitable replacement for a sulfoxide or
sulfone linker in this series.
Permeability, metabolic stability and CYP450 inhibition
studies
Compound 31 was evaluated for its membrane permeability
using the Caco-2 cell model. The apparent permeability coeffi-
cient (Papp) from apical to basolateral side was measured at a
concentration of 20 mm; the result indicates that the com-
pound is of high permeability (Papp(A>B)=6.3ꢁ10 ꢀ6), suggest-
ing that 31 may have a good oral absorption property.
To identify compounds with high 11b-HSD1 inhibitory activi-
ty against both human and mouse enzymes, we selected com-
pounds with IC50 values below 50 nm on human 11b-HSD1 and
examined their activity against the mouse enzyme. Com-
pounds 16, 28, 31 and 43 all exhibit high potency against the
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1621

B. V. L. Potter et al.
MED
Docking studies
Table 9. Metabolism studies in human liver microsomes.[a]
1
2
Compd
t [min]
CLint [mLminꢀ1 mgꢀ1
]
To investigate the potential binding mode of the inhibitor,
compound 12 was docked into the X-ray crystal structure of
human 11b-HSD1 (PDB: 2ILT[45]) using the GOLD docking pro-
gram (v4.1). Ranked by the docking score, the top five predict-
ed poses are almost identical. The pyridyl motif is placed close
to the cofactor with the pyridyl nitrogen being 3.5 ꢂ away
16
28
31
42
20
68
128
34
31
8.9
3.7
19
[a] The parent compound was incubated at 378C with human liver micro-
somes in the presence of the cofactor NADPH for 40 min. Disappearance
1
of the parent compound was monitored using HPLC. Half-life (t ) and in-
2
trinsic clearance (CLint) values were calculated accordingly.[44] Data are the
mean value of two measurements.
Metabolic stability is a critical factor in the selection of com-
pounds for further preclinical studies. Potent inhibitors 16, 28,
31 and 42 were incubated with human liver microsomes to
evaluate their stability under such conditions (Table 9). Two
compounds (16 and 42) with a sulfoxide linker underwent
rapid metabolism when incubated at 378C with human liver
microsomes in the presence of the cofactor NADPH. With a
1
half-life (t ) of only 20–30 min and a high intrinsic clearance
2
rate, these compounds are not suitable for in vivo study. On
the other hand, 2-pyridyl derivative 28 shows enhanced meta-
1
2
bolic stability with a t of 68 min and an intrinsic clearance of
Figure 2. Best docking solution of compound 12 (in cyan) with the cofactor
(in purple) and active residues (in green).
8.9 mLminꢀ1 mgꢀ1. Furthermore, compound 31, with the same
ethanone ether linker and a 3-pyridyl ring, exhibits even great-
1
er metabolic stability, displaying a t of more than 2 h and a
2
clearance rate of 3.7 mLminꢀ1 mgꢀ1, indicating that metabolic
from the NH2 group of the nicotinamide moiety. The carbonyl
group possibly forms hydrogen-bond interactions with the hy-
droxy group of Ser170 (2.3 ꢂ) and/or Tyr183 (2.6 ꢂ). The ether
oxygen could also form contacts with the protein through
Tyr183 (2.8 ꢂ). The hydrophobic adamantyl group is predicted
to stack with Tyr177 at a distance of ~3.5 ꢂ (Figure 2).
stability may be achieved with this structural core. There were
Table 10. Inhibition of human cytochrome P450 enzymes by selected
compounds (18, 28, 31, 43).
IC50 [mm][a]
Docking studies with 28 and 31 reveal that the best poses
of these two compounds overlap nicely with each other. The
adamantyl moiety is predicted to form hydrophobic contacts
with Tyr177 in a distance of ~3.5 ꢂ in both cases. The carbonyl
groups from 28 and 31 being 2.8 ꢂ and 2.6 ꢂ away from the
hydroxy group of the catalytic residue Tyr183, respectively, are
able to act as hydrogen-bond acceptors. In addition, the hy-
CYP450
18
28
31
23
>100
46
ND
68
1.6
43
36
>100
24
ND
>100
24
1A2
2C9
2C19
2D6
3A4-BFC
3A4-BQ
>100
>100
>100
>100
12
>100
>100
>100
>100
20
>100
78
[a] Values are reported as the mean of two measurements; ND: not deter-
mined.
no metabolites identified for compounds 28 and 31 under
such conditions.
Compounds 18, 28, 31 and 43 were also examined for their
inhibition of the key human cytochrome P450 enzymes: 1A2,
2C9, 2C19, 2D6, 3A4-BFC and 3A4-BQ (Table 10). These results
may help identify potential problems with these compounds
interfering with the metabolism of other drugs. All compounds
tested display very weak activity against these cytochrome
P450 enzymes, except compound 31 that shows a moderate
inhibition of 3A4-BQ with an IC50 value of 1.6 mm, which is
greater than 30-fold of its inhibitory activity against 11b-HSD1.
Figure 3. Best docking pose for compounds 28 (in cyan) and 31 (in buff)
with the cofactor (in purple) and active residues (in green).
1622
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
droxy group of Ser170 could form a hydrogen bond to the
carbonyl group of 28 and 31 in a distance of 3.4 ꢂ and 3.1 ꢂ,
respectively. The ether oxygen in the linker of 28 and 31 is
placed 3.3 ꢂ and 3.4 ꢂ, respectively, away from the phenolic
group on the catalytic residue Tyr183, suggesting possible hy-
drogen-bond interactions between them (Figure 3).
show only very weak inhibition of key human CYP450 en-
zymes. Results from in vitro studies suggest that these com-
pounds may be worthy of further preclinical investigation.
Experimental Section
A docking study with compound 43 shows the highest rank-
ing solution positioning the molecule in a pose similar to that
of compounds 28 and 31. The adamantyl motif is predicted to
interact with the protein through hydrophobic interactions
with Tyr177 and Leu217. The carbonyl group, being 2.7 ꢂ
Cellular 11b-HSD1 inhibition assay with scintillation proximity assay
(SPA) protocol:[46] Wild-type HEK293 cells lack endogenous 11b-
HSD1 activity, and this cell line has been shown to be a suitable
system for evaluating 11b-HSD1 activity after transfection with the
plasmid for 11b-HSD1 or 11b-HSD2 expression.[47] The enzyme ac-
tivity was determined by measuring the amount of tritiated prod-
uct using a scintillation proximity assay (SPA). The high-throughput
cell-based assays were conducted on the HEK293 cell line stably
transfected with the HSD11B1 gene using modified literature proto-
cols. Cells were incubated in 96-well microplates in the presence of
tritiated substrate, and the assay plates contained internal high
and low controls to allow calculation of inhibition as a percentage.
Each well of a 96-well culture plate was seeded with HEK293/
HSD11B1 cells (2ꢁ104 cells per well) in 100 mL medium. When the
cell culture was 80% confluent, the medium was removed from
each well and replaced with 100 mL of fresh, serum-free, medium
containing [3H]cortisone (10 mL of [3H]cortisone stock 51 cimmolꢀ1),
and test compound in 1% DMSO was added to each well. The
final substrate concentration was ~0.5 cimmolꢀ1. The control wells
were also dispensed. The high control wells did not contain com-
pound, while low controls did not contain cells. The plate was in-
cubated at 378C for 2 h, after which, 50 mL of media was removed
from each well and transferred to a microplate containing 100 mL
of a preincubated mixture of anticortisol antibody and SPA bead.
The mixture was incubated with gentle shaking until equilibrium
was reached, before transferring to a scintillation counter to estab-
lish the enzyme activity in each sample.
Figure 4. Best docking pose for compound 43 (in cyan) with the cofactor (in
purple) and active residues (in green).
away from Tyr183, is most likely acting as a hydrogen-bond ac-
ceptor. One of the sulfone oxygen atoms is predicted to be
close to the hydroxy group of residue Tyr183 (2.7 ꢂ) with
which it may form a hydrogen bond. The other sulfone oxygen
may be involved in a hydrogen bond to Thr124 (3.1 ꢂ)
(Figure 4).
Docking study procedure: Selected ligands were docked into the
11b-HSD1 protein X-ray crystal structure PBD: 2ILT[45] using the
GOLD docking program (v4.1) with default settings in the presence
of the cofactor. The binding site was defined as a sphere of 10 ꢂ
radius 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.
Conclusions
In summary, adamantyl ethanone pyridyl derivatives have been
identified as potent and selective inhibitors of human and
mouse 11b-HSD1. Eleven compounds display high inhibitory
activities against 11b-HSD1, with IC50 values below 50 nm
when evaluated on a stably transfected HEK-293 cell line. They
are also highly selective 11b-HSD1 inhibitors, with no activity
against 11b-HSD2 and 17b-HSD1. Structure–activity relation-
ship studies reveal that a pyridyl ring tethered to an adamantyl
ethanone moiety through an oxygen, sulfoxide or sulfone
linker represents a suitable pharmacophore for inhibitory activ-
ity. A substitution on the pyridyl ring normally results in a loss
of activity, as most of the highly potent compounds in this
series contain a unsubstituted pyridine ring. The inhibitors
with a sulfoxide linker are consistently highly potent regardless
of the linker length, suggesting important interactions of the
S=O group in the enzyme pocket. Compounds 28 and 31, with
an ethanone ether linker, are not only potent 11b-HSD1 inhibi-
tors of both the human and mouse enzyme, but are also rela-
tively stable when incubated in human liver microsomes and
Chemistry
General methods: All chemicals were purchased from either Al-
drich Chemical Co. (Gillingham, UK) or Alfa Aesar (Heysham, UK).
All organic solvents of AR grade were supplied by Fisher Scientific
(Loughborough, UK). Melting points were determined using a Stan-
ford Research Systems Optimelt MPA100 and are uncorrected.
Compounds in solid form were crystallised from CH2Cl2/EtOAc.
Thin layer chromatography (TLC) was performed on precoated alu-
minium plates (Merck, silica gel 60 F254). Products were visualised
by UV irradiation at 254 nm and by staining with 5% w/v molybdo-
phosphoric acid in EtOH, followed by heating. Flash column chro-
matography was performed on prepacked columns (RediSep RF)
and gradient elution (solvents indicated in text) on the Combiflash
1
RF system (Teledyne Isco). H NMR spectra were recorded on a Jeol
Delta 270 MHz spectrometer. Chemical shifts (d) are reported in
parts per million (ppm) relative to tetramethylsilane (TMS) as an in-
ternal standard. LC/MS spectra were recorded on a Waters 2790 in-
strument using a Waters Symmetry C18 column (packing: 3.5 mm,
4.6 mmꢁ75 mm) eluting with 10% H2O/CH3OH (1 mLminꢀ1), and
detected with a ZQ MicroMass spectrometer and PDA detector
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1623

B. V. L. Potter et al.
MED
using atmospheric pressure chemical ionisation (APCI) or electro-
spray ionisation (ESI). High-resolution mass spectra were recorded
on a Bruker MicroTOF with ESI or at the EPSRC National Mass Spec-
trometry Service (Swansea, UK) with fast atom bombardment (FAB)
using m-nitrobenzyl alcohol (NBA) as the matrix. HPLC was under-
taken using a Waters 717 machine with Autosampler and PDA de-
tector. The column used was a Waters Symmetry C18 (packing:
3.5 mm, 4.6 mmꢁ150 mm) with an isocratic mobile phase consist-
(FAB): m/z [M+H]+ calcd for C18H24NO2: 286.1807, found:
286.1800; HPLC: tR =6.2 min (97%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridin-3-yloxy)ethan-1-one (12): An off-
white solid (78%); mp: 73–758C; 1H NMR (270 MHz, CDCl3): d=
1.75–1.82 (m, 6H), 1.92 (d, J=2.7 Hz, 6H), 2.08 (brs, 3H), 4.91 (s,
2H), 7.10–7.21 (m, 2H), 8.22 (dd, J=4.6, 1.3 Hz, 1H), 8.26 ppm (d,
J=2.7 Hz, 1H); LC/MS (ESI): m/z: 270 [MꢀH]+; HRMS (ESI): m/z
[M+H]+ calcd for C17H22NO2: 272.1651, found: 272.1672; HPLC:
tR =2.4 min (97%) in 10% H2O/CH3CN.
ing of H2O/CH3CN at a flow rate of 1.0 mLminꢀ1
.
Method A: Synthesis of adamantyl ethanone pyridyl ether com-
pounds 6–12: A suspension of K2CO3 (2 equiv) in acetone (10 mL)
was treated with the corresponding hydroxypyridine (1 equiv), fol-
lowed by adamantan-1-yl bromomethyl ketone (1 equiv). The mix-
ture was stirred at RT overnight. After quenching with water
(20 mL), the mixture was extracted twice with EtOAc (30 mL). The
organic phase was washed with brine, dried (MgSO4), filtered and
concentrated in vacuo. The crude product was purified with flash
chromatography (hexane/EtOAc or CH2Cl2/EtOAc; gradient elution).
Method B: Synthesis of the adamantyl ethanone sulfanyl deriva-
tives 13–15: A solution of adamantan-1-yl bromomethyl ketone
(1 equiv) in CH3CN (10 mL) was treated with the corresponding
mercaptan (1.1 equiv), followed by Et3N (3 equiv). The mixture was
stirred at RT overnight. 2-Chloro-tritylchloride resin (1.1 equiv,
1.6 mmolgꢀ1) was added and the mixture was stirred for 2 h, fil-
tered and concentrated in vacuo. Purification using flash chroma-
tography (hexane/EtOAc or CH2Cl2/EtOAc; gradient elution) gave
the target compound.
1-(Adamantan-1-yl)-2-[(6-methylpyridin-2-yl)oxy]ethan-1-one (6):
A white solid (69%); mp: 85–878C; H NMR (270 MHz, CDCl3): d=
1-(Adamantan-1-yl)-2-(pyridin-2-ylsulfanyl)ethan-1-one (13):
A
1
white solid (99%); mp: 60–618C; 1H NMR (270 MHz, CDCl3): d=
1.68–1.79 (m, 6H), 1.94 (d, J=2.7 Hz, 6H), 2.07 (brs, 3H), 4.23 (s,
2H), 6.93 (ddd, J=7.4, 4.9, 1.0 Hz, 1H), 7.21 (dt, J=8.2, 1.0 Hz, 1H),
7.44 (ddd, J=9.2, 7.4, 2.0 Hz, 1H), 8.32 (dq, J=4.9, 1.0 Hz, 1H); LC/
MS (ESI): m/z: 288 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for
C17H22NOS: 288.1422, found: 288.1431; HPLC: tR =3.6 min (>99%)
in 10% H2O/CH3CN.
1.68–1.81 (m, 6H), 1.94 (brs, 6H), 2.05 (brs, 3H), 2.32 (s, 3H), 5.10
(s, 2H), 6.45 (dd app, J=7.2, 3.9 Hz, 2H), 7.42 ppm (t, J=7.7 Hz,
1H); LC/MS (APCI): m/z: 286 [M+H]+; HRMS (FAB): m/z [M+H]+
calcd for C18H24NO2: 286.1807, found: 286.1804; HPLC: tR =8.9 min
(>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(6-chloropyridin-2-yl)oxy]ethan-1-one (7):
1
A white solid (99%); mp: 90–938C; H NMR (270 MHz, CDCl3): d=
1-(Adamantan-1-yl)-2-[(6-methylpyridin-2-yl)sulfanyl]ethan-1-
1.65–1.82 (m, 6H), 1.93 (d, J=2.5 Hz, 6H), 2.06 (brs, 3H), 5.10 (s,
2H), 6.76 (d, J=8.3 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 7.51 ppm (t, J=
8.3 Hz, 1H); LC/MS (APCI): m/z: 328 [M+Na]+; HRMS (FAB): m/z
[M+H]+ calcd for C17H21ClNO2: 306.1261, found: 306.1261; HPLC:
tR =4.0 min (>99%) in 10% H2O/CH3CN.
1
one (14): A white solid (89%); mp: 116–1178C; H NMR(270 MHz,
CDCl3): d=1.68–1.82 (m, 6H), 1.95 (d, J=2.7 Hz, 6H), 2.07 (brs,
3H), 2.43 (s, 3H), 4.22 (s, 2H), 6.78 (d, J=7.9 Hz, 1H), 7.03 (d, J=
7.9 Hz, 1H), 7.33 ppm (t, J=7.9 Hz, 1H); LC/MS (ESI): m/z: 302 [M+
H]+; HRMS (ESI): m/z [M+H]+ calcd for C18H24NOS: 302.1579,
found: 302.1583; HPLC: tR =4.5 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}ethan-
1-one (8): A white solid (90%); mp: 102–1048C; 1H NMR (270 MHz,
CDCl3): d=1.65–1.83 (m, 6H), 1.93 (d, J=2.7 Hz, 6H), 2.08 (brs,
3H), 4.85 (s, 2H), 6.58 (brd, J=10.4 Hz, 1H), 7.40–7.48 ppm (m,
2H); LC/MS (APCI): m/z 338 [MꢀH]+; HRMS (FAB): m/z [M+H]+
calcd for C18H21F3NO2 340.1524, found: 340.1521; HPLC: tR =2.2 min
(99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridin-4-ylsulfanyl)ethan-1-one (15):
A
1
white solid (86%); mp: 114–1158C; H NMR (270 MHz, CDCl3): d=
1.70–1.82 (m, 6H), 1.90 (d, J=2.8 Hz, 6H), 2.08 (brs, 3H), 4.01 (s,
2H), 7.08 (dd, J=4.7, 1.8 Hz, 2H), 8.38 ppm (dd, J=4.7, 1.8 Hz, 2H);
LC/MS (ESI): m/z: 288 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for
C17H22NOS: 288.1422, found: 288.1420; HPLC: tR =2.6 min (>99%)
in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(5-chloropyridin-3-yl)oxy]ethan-1-one (9):
An off-white solid (76%); mp: 127–1288C; 1H NMR (270 MHz,
CDCl3): d=1.63–1.82 (m, 6H), 1.88 (d, J=2.5 Hz, 6H), 2.07 (brs,
3H), 4.89 (s, 2H), 7.06–7.12 (m, 1H), 8.12 (d, J=2.2 Hz, 1H),
8.17 ppm (d, J=1.4 Hz, 1H); LC/MS (APCI): m/z: 328 [M+Na]+;
HRMS (FAB): m/z [M+H]+ calcd for C17H21ClNO2: 306.1261, found:
306.1244; HPLC: tR =2.8 min (>99%) in 10% H2O/CH3CN.
Method C: Synthesis of the adamantyl ethanone sulfoxide and
sulfone derivatives 16–21: A cold solution of the corresponding
sulfanyl derivative (1 equiv) in CH2Cl2 (10 mL) was treated with m-
CPBA (2.5 equiv) and stirred at ꢀ108C!08C for 1 h. The reaction
was partitioned between CH2Cl2 and 5% aq NaHCO3, then separat-
ed. The organic phase was washed with brine, dried (MgSO4), fil-
tered and concentrated in vacuo. The sulfoxide and sulfone were
separated using flash chromatography (EtOAc/CH2Cl2; gradient elu-
tion).
1-(Adamantan-1-yl)-2-[(2-chloropyridin-3-yl)oxy]ethan-1-one
1
(10): An off-white solid (98%); mp: 125–1288C; H NMR (270 MHz,
CDCl3): d=1.63–1.82 (m, 6H), 1.88 (d, J=2.8 Hz, 6H), 2.05 (brs,
3H), 4.94 (s, 2H), 6.92 (dd, J=8.0, 1.4, Hz, 1H), 7.10 (dd, J=8.0,
4.7 Hz, 1H), 7.96 (dd, J=4.7, 1.4 Hz, 1H); LC/MS (APCI): m/z: 328
[M+Na]+; HRMS (FAB): m/z [M+H]+ calcd for C17H21ClNO2:
306.1261, found: 306.1246; HPLC: tR =2.4 min (>99%) in 10%
H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridine-2-sulfinyl)ethan-1-one (16):
A
white solid (65%); mp: 66–688C; 1H NMR (270 MHz, CDCl3): d=
1.58–1.76 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.04 (brs, 3H), 4.05(d,
J=15.6 Hz, 1H), 4.32 (d, J=15.6 Hz, 1H), 7.38 (m, 1H), 7.90–8.20 (m,
2H), 8.61 ppm (dq, J=5.1, 0.8 Hz, 1H); LC/MS (ESI): m/z: 302
[MꢀH]+; HRMS (FAB): m/z [M+H]+ calcd for C17H22NO2S: 304.1371,
found: 304.1366; HPLC: tR =2.2 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(6-methylpyridin-3-yl)oxy]ethan-1-one
(11): An off-white solid (80%); mp: 86–878C; 1H NMR (270 MHz,
CDCl3): d=1.67–1.82 (m, 6H), 1.90 (brd, J=3.0 Hz, 6H), 2.02–2.11
(brs, 3H), 2.47 (s, 3H), 4.87 (s, 2H), 7.00–7.10 (m, 2H), 8.12 ppm
(dd, J=2.5, 1.2 Hz, 1H); LC/MS (APCI): m/z: 286 [M+H]+; HRMS
1-(Adamantan-1-yl)-2-(pyridine-2-sulfonyl)ethan-1-one (19):
A
1
white solid (25%); mp: 129–1318C; H NMR (270 MHz, CDCl3): d=
1.54–1.76 (m, 12H), 2.04 (brs, 3H), 4.67 (s, 2H), 7.53 (ddd, J=7.8,
1624
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
4.9, 1.8 Hz, 1H), 7.97 (td, J=7.7, 1.8 Hz, 1H), 8.08 (dt, J=8.0, 1.0 Hz,
1H), 8.70 ppm (dq, J=5.0, 0.8 Hz, 1H); LC/MS (ESI): m/z: 318
[MꢀH]+; HRMS (ESI): m/z [M+H]+ calcd for C17H22NO3S: 320.1320,
found: 320.1315; HPLC: tR =2.1 min (>99%) in 10% H2O/CH3CN.
(270 MHz, CDCl3): d=1.69–1.82 (m, 6H), 1.95 (d, J=2.7 Hz, 6H),
2.08 (brs, 3H), 4.24 (s, 2H), 5.98 (brs, 2H), 7.26 (d, J=8.5 Hz, 1H),
7.86 (dd, J=8.6, 2.5 Hz, 1H), 8.72 ppm (d, J=2.2 Hz, 1H); LC/MS
(ESI): m/z: 331 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for
C18H23N2O2S: 331.1480, found: 331.1464; HPLC: tR =2.2 min (99%)
in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(6-methylpyridine-2-sulfinyl)ethan-1-one
1
(17): A white solid (69%); mp: 75–768C; H NMR (270 MHz, CDCl3):
6-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}-N-methylpyridine-3-
carboxamide (25): A white solid (46%); mp: 184–1868C; H NMR
d=1.59–1.76 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.04 (brs, 3H), 2.57
(s, 3H), 4.03 (d, J=15.4 Hz, 1H), 4.26 (d, J=15.4 Hz, 1H), 7.21 (t, J=
4.4 Hz, 1H), 7.80 ppm (d, J=4.4 Hz, 2H); LC/MS (ESI): m/z: 318
[M+H]+; HRMS (ESI): m/z [M+H]+ calcd for C18H24NO2S: 318.2518,
found: 318.2515; HPLC: tR =2.5 min (>99%) in 10% H2O/CH3CN.
1
(270 MHz, CDCl3): d=1.63–1.80 (m, 6H), 1.94 (d, J=2.7 Hz, 6H),
2.07 (brs, 3H), 2.97 (d, J=5.0 Hz, 3H), 4.23 (s, 2H), 6.22 (brs, 1H),
7.22 (d, J=8.7 Hz, 1H), 7.80 (dd, J=8.7, 1.6 Hz, 1H), 8.66 ppm (d,
J=1.6 Hz, 1H); LC/MS (ESI): m/z: 345 [M+H]+; HRMS (ESI): m/z
[M+H]+ calcd for C19H25N2O2S: 345.1637, found: 345.1623; HPLC:
tR =2.4 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(6-methylpyridine-2-sulfonyl)ethan-1-one
(20): A white solid (17%); mp: 151–1528C; 1H NMR (270 MHz,
CDCl3): d=1.56–1.72 (m, 6H), 1.77 (d, J=2.7 Hz, 6H), 2.05 (brs,
3H), 2.60 (s, 3H), 4.67 (s, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.82 (t, J=
7.4 Hz, 1H), 7.89 ppm (d, J=7.6 Hz, 1H); LC/MS (ESI): m/z: 334
[M+H]+; HRMS (ESI): m/z [M+H]+ calcd for C18H24NO3S: 334.1477,
found: 334.1458; HPLC: tR =2.6 min (>99%) in 10% H2O/CH3CN.
6-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}-N-ethylpyridine-3-
1
carboxamide (26): A white solid (81%); mp: 136–1378C; H NMR
(270 MHz, CDCl3): d=1.22 (t, J=7.2 Hz, 3H), 1.68–1.79 (m, 6H),
1.93 (d, J=2.7 Hz, 6H), 2.07 (brs, 3H), 3.46 (m, 2H), 4.23 (s, 2H),
6.15 (s, 1H), 7.22 (dd, J=8.6, 1.0 Hz, 1H), 7.80 (dd, J=8.2, 2.2 Hz,
1H), 8.66 ppm (d, J=1.6 Hz, 1H); LC/MS (ESI): m/z: 359 [M+H]+;
HRMS (ESI): m/z [M+H]+ calcd for C20H27N2O2S: 359.1793, found:
359.1773; HPLC: tR =2.6 min (98%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridine-4-sulfinyl)ethan-1-one (18):
A
1
white solid (77%); mp: 136–1388C; H NMR (270 MHz, CDCl3): d=
1.60–1.68 (m, 6H), 1.74 (d, J=2.7 Hz, 6H), 2.02 (brs, 3H), 3.86 (d,
J=15.7 Hz, 1H), 4.21 (d, J=15.7 Hz, 1H), 7.62 (dd, J=4.7, 1.3 Hz,
2H), 8.78 ppm (dd, J=4.7, 1.4 Hz, 2H); LC/MS (ESI): m/z: 304 [M+
H]+; HRMS (ESI): m/z [M+H]+ calcd for C17H22NO2S: 304.1371,
found: 304.1359; HPLC: tR =2.0 min (>99%) in 10% H2O/CH3CN.
6-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}-N,N-dimethylpyri-
dine-3-carboxamide (27): A white solid (70%); mp: 63–658C;
1H NMR (270 MHz, CDCl3): d=1.65–1.79 (m, 6H), 1.94 (d, J=2.7 Hz,
6H), 2.07 (brs, 3H), 3.02 (s, 3H), 3.07 (s, 3H), 4.23 (s, 2H), 7.24 (dd,
J=8.3, 0.8 Hz, 1H), 7.53 (dd, J=8.3, 2.2 Hz, 1H), 8.41 ppm (dd, J=
2.2, 0.8 Hz, 1H); LC/MS (ESI): m/z: 359 [M+H]+; HRMS (ESI): m/z
[M+H]+ calcd for C20H27N2O2S: 359.1793, found: 359.1778; HPLC:
tR =2.6 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridine-4-sulfonyl)ethan-1-one (21):
A
1
white solid (16%); mp: 143–1448C; H NMR (270 MHz, CDCl3): d=
1.61–1.70 (m, 6H), 1.74 (d, J=2.7 Hz, 6H), 2.05 (brs, 3H), 4.33 (s,
2H), 7.79 (dd, J=4.7, 1.4 Hz, 2H), 8.90 ppm (dd, J=4.7, 1.4 Hz, 2H);
LC/MS (ESI): m/z: 320 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for
C17H22NO3S: 320.1320, found: 320.1304; HPLC: tR =2.1 min (>99%)
in 10% H2O/CH3CN.
Method E: Synthesis of ethanone ether linker compounds 28–
34: A suspension of NaH (60% in mineral oil, 1.2 equiv) in dry THF
(5 mL) was treated with the pyridylmethanol (1.0 equiv) at 08C.
After stirring for 30 min, 1-adamantyl bromomethyl ketone
(1.1 equiv) was added in dry THF (5 mL). The reaction was stirred
for 2 h at 08C then at RT overnight. After quenching with water,
the mixture was extracted twice with Et2O, washed with water
then brine, dried (MgSO4), filtered and concentrated in vacuo. The
crude product was purified using flash chromatography (CH2Cl2/
CH3OH; gradient elution).
Compounds 22–23 were synthesized using Method B:
1-(Adamantan-1-yl)-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfanyl}e-
than-1-one (22): A white solid (86%); mp: 141–1428C; 1H NMR
(270 MHz, CDCl3): d=1.69–1.80 (m, 6H), 1.94 (d, J=2.7 Hz, 6H),
2.08 (brs, 3H), 4.26 (s, 2H), 7.30 (t, J=8.6 Hz, 1H), 7.64 (dd, J=8.5,
2.5 Hz, 1H), 8.55 ppm (s, 1H); LC/MS (ESI): m/z: 354 [MꢀH]+; HRMS
(ESI): m/z [M+Na]+ calcd for C18H20F3NOSNa: 378.1115, found:
378.1090; HPLC: tR =6.6 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridin-2-ylmethoxy)ethan-1-one (28):
A
clear oil (64%); 1H NMR (270 MHz, CDCl3): d=1.60–1.80 (m, 6H)
1.81 (d, J=2.7 Hz, 6H), 2.01 (brs, 3H), 4.43 (s, 2H), 4.67 (s, 2H),
7.13–7.21 (m, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.69 (td, J=7.6, 1.7 Hz,
1H), 8.53 ppm (dq, J=5.0, 0.8 Hz, 1H); LC/MS (APCI): m/z: 286
[M+H]+; HRMS (FAB): m/z [M+H]+ calcd for C18H24NO2: 286.1807,
found: 286.1796; HPLC: tR =5.6 min (>99%) in 10% H2O/CH3CN.
6-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}pyridine-3-carboxylic
acid (23): A white solid (65%); mp: 174–1768C; H NMR (270 MHz,
1
CDCl3): d=1.65–1.80 (m, 6H), 1.95 (d, J=2.7 Hz, 6H), 2.00 (brs,
3H), 4.28 (s, 2H), 7.31 (dd, J=8.6, 0.7 Hz, 1H), 8.06 (dd, J=8.6,
2.2 Hz, 1H), 8.97 ppm (dd, J=2.2, 0.7 Hz, 1H); LC/MS (ESI): m/z:
332 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for C18H22NO3S:
332.1320, found: 332.1302; HPLC: tR =1.6 min (97%) in 10% H2O/
CH3CN.
1-(Adamantan-1-yl)-2-[(6-methylpyridin-2-yl)methoxy]ethan-1-
1
one (29): An off-white semi-solid (43%); H NMR (270 MHz, CDCl3):
Method D: Synthesis of the carboxamide derivatives 24–27: A
solution of carboxylic acid 23 (1.0 equiv) in CH2Cl2 (5 mL) was treat-
ed with EDCI (1.2 equiv), HOBt (0.5 equiv), Et3N (1.2 equiv) and
DMAP (catalytic amount) at RT. After stirring for 30 min, the amine
(1.2 equiv) was added, and the reaction mixture was stirred over-
night and then extracted twice with CH2Cl2. The organic phase was
washed with 5% aq NaHCO3 and brine, dried (MgSO4), filtered and
concentrated in vacuo. The crude product was purified using flash
chromatography with EtOAc/CH2Cl2 gradient elution.
d=1.60–1.80 (m, 6H), 1.81 (d app, J=3.0 Hz, 6H), 2.02 (brs, 3H),
2.52 (s, 3H), 4.42 (s, 2H), 4.64 (s, 2H), 7.42 (d app, J=7.4 Hz, 1H),
7.31 (d app, J=7.7 Hz, 1H), 7.58 ppm (t, J=7.7 Hz, 1H); LC/MS
(APCI): m/z: 300 [M+H]+; HRMS (FAB): m/z [M+H]+ calcd for
C19H26NO2: 300.1964, found: 300.1950; HPLC: tR =5.9 min (>99%)
in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(3-methoxypyridin-2-yl)methoxy]ethan-1-
1
one (30): A yellow oil (66%); H NMR (270 MHz, CDCl3): d=1.55–
1.78 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.01 (brs, 3H), 3.82 (s, 3H),
4.31 (s, 2H), 4.55 (s, 2H), 7.15 (dd, J=7.9, 2.0 Hz, 1H), 7.27 (t, J=
7.7 Hz, 1H), 8.26 ppm (dd, J=7.9, 2.1 Hz, 1H); LC/MS (APCI): m/z:
6-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}pyridine-3-carboxa-
mide (24):
A
white solid (55%); mp: 172–1748C; 1H NMR
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1625

B. V. L. Potter et al.
MED
316 [M+H]+; HRMS (FAB): m/z [M+H]+ calcd for C19H26NO3:
316.1913, found: 316.1897; HPLC: tR =2.3 min (97%) in 10% H2O/
CH3CN.
with NaOH (160 mg, 4.0 mmol). The mixture was stirred at 808C
under N2 for 45 min, cooled to RT and added to a solution of 5
(514 mg, 2.0 mmol) in CH3CN/Et3N (3 mL/2 mL). The mixture was
stirred at RT overnight, then partitioned between CH2Cl2 and water.
The organic phase was washed brine, dried (MgSO4), filtered and
concentrated. Purification using flash chromatography (EtOAc/
hexane; gradient elution) gave the desired compound.
1-(Adamantan-1-yl)-2-(pyridin-3-ylmethoxy)ethan-1-one
(31):
1
Off-white crystals (48%); mp: 67–688C; H NMR (270 MHz, CDCl3):
d=1.58–1.78 (m, 6H), 1.80 (d, J=3.0 Hz, 6H), 2.01 (brs, 3H), 4.34
(s, 2H), 4.56 (s, 2H), 7.27 (dd, J=7.9, 4.9 Hz, 1H), 7.74 (td, J=7.9,
2.0 Hz, 1H), 8.56 ppm (m, 2H); LC/MS (APCI): m/z: 286 [M+H]+;
HRMS (FAB): m/z [M+H]+ calcd for C18H24NO2: 286.1807, found:
286.1796; HPLC: tR =5.6 min (> 99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfanyl]ethan-1-one
(37): An off-white solid (550 mg, 91%); mp: 38–398C; 1H NMR
(270 MHz, CDCl3): d=1.61–1.75 (m, 6H), 1.81 (d, J=2.7 Hz, 6H),
2.02 (brs, 3H), 3.38 (s, 2H), 3.83 (s, 2H), 7.15 (ddd, J=7.6, 4.8,
1.0 Hz, 1H), 7.36 (dt, J=7.8, 1.0 Hz, 1H), 7.63 (td, J=7.6, 1.7 Hz,
1H), 8.54 ppm (dq, J=5.0, 1.0 Hz, 1H); LC/MS (ESI): m/z: 302 [M+
H]+; HRMS (ESI): m/z [M+H]+ calcd for C18H24NOS: 302.1579,
found: 302.1585; HPLC: tR =2.8 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(4-methoxypyridin-3-yl)methoxy]ethan-1-
1
one (32): An off-white semi-solid (29%); H NMR (270 MHz, CDCl3):
d=1.59–1.75 (m, 6H), 1.77 (d, J=2.8 Hz, 6H), 1.99 (brs, 3H), 3.89
(s, 3H), 4.26 (s, 2H), 4.46 (s, 2H), 6.71 (d, J=8.5 Hz, 1H), 7.63 (dd,
J=8.5, 2.5 Hz, 1H), 8.06 ppm (d, J=2.5 Hz, 1H); LC/MS (APCI): m/z:
316 [M+H]+; HRMS (FAB): m/z [M+H]+ calcd for C19H26NO3:
316.1913, found: 316.1923; HPLC: tR =2.9 min (97%) in 10% H2O/
CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-3-ylmethyl)sulfanyl]ethan-1-one
(38): An off-white solid (320 mg, 53%); mp: 45–478C; 1H NMR
(270 MHz, CDCl3): d=1.62–1.75 (m, 6H), 1.80 (d, J=2.7 Hz, 6H),
2.02 (brs, 3H), 3.21 (s, 2H), 3.71 (s, 2H), 7.24 (dd, J=7.7, 4.7 Hz,
1H), 7.69 (dt, J=7.7, 1.8 Hz, 1H), 8.49 (dd, J=4.7, 1.7 Hz, 1H),
8.53 ppm (d, J=2.2 Hz, 1H); LC/MS (ESI): m/z: 302 [M+H]+; HRMS
(ESI): m/z [M+H]+ calcd for C18H24NOS: 302.1579, found: 302.1583;
HPLC: tR =2.7 min (99%) in 10% H2O/CH3CN
1-(Adamantan-1-yl)-2-[(5-methoxypyridin-3-yl)methoxy]ethan-1-
1
one (33): A light yellow oil (43%); H NMR (270 MHz, CDCl3): d=
1.81–1.56 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.02 (brs, 3H), 3.85 (s,
3H), 4.33 (s, 2H), 4.56 (s, 2H), 7.29 (s, 1H), 8.14 (s, 1H), 8.24 ppm
(d, J=3.0 Hz, 1H); LC/MS (APCI): m/z: 316 [M+H]+; HRMS (FAB):
m/z [M+H]+ calcd for C19H26NO3: 316.1913, found: 316.1907;
HPLC: tR =2.2 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-4-ylmethyl)sulfanyl]ethan-1-one
(39): A yellow oil (331 mg, 55%); 1H NMR (270 MHz, CDCl3): d=
1.62–1.75 (m, 6H), 1.78 (d, J=2.7 Hz, 6H), 2.01 (brs, 3H), 3.17 (s,
2H), 3.66 (s, 2H), 7.24 (d, J=5.1 Hz, 2H), 8.53 ppm (d, J=5.1 Hz,
2H); LC/MS (ESI): m/z: 302 [M+H]+; HRMS (ESI): m/z [M+H]+
calcd for C18H24NOS: 302.1579, found: 302.1577; HPLC: tR =3.1 min
(97%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[6-(trifluoromethyl)pyridin-3-yl]methox-
1
y}ethan-1-one (34): A white solid (29%); mp: 106–1098C; H NMR
(270 MHz, CDCl3): d=1.58–1.80 (m, 6H), 1.80 (d, J=2.7 Hz, 6H),
2.01 (brs, 3H), 4.38 (s, 2H), 4.63 (s, 2H), 7.65 (d, J=7.9 Hz, 1H),
7.93 (dd, J=7.9, 1.4 Hz, 1H), 8.65 ppm (brs, 1H); LC/MS (APCI): m/
z: 376.0 [M+Na]+; HRMS (FAB+): m/z [M+H]+ calcd for
C19H23F3NO2: 354.1681, found: 354.1664; HPLC: tR =3.2 min (97%)
in 10% H2O/CH3CN.
Compounds 40–45 were synthesized using Method C:
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfinyl]ethan-1-one
1
(40): A white solid (52%); mp: 87–888C; H NMR (270 MHz, CDCl3):
d=1.69–1.79 (m, 6H), 1.80 (d, J=2.7 Hz, 6H), 2.05 (brs, 3H), 3.87
(d, J=15.9 Hz, 1H), 4.02 (d, J=15.9 Hz, 1H), 4.19 (d, J=12.9 Hz,
1H), 4.36 (d, J=12.9 Hz, 1H), 7.25 (ddd, J=7.6, 4.9, 0.9 Hz, 1H),
7.35 (d, J=7.7 Hz, 1H), 7.70 (td, J=7.6, 1.7 Hz, 1H), 8.60 ppm (dq,
J=5.0, 0.7 Hz, 1H); LC/MS (ESI): m/z: 340 [M+Na]+; HRMS (FAB):
m/z [M+H]+ calcd for C18H24NO2S: 318.1528, found: 318.1521;
HPLC: tR =1.9 min (>99%) in 10% H2O/CH3CN.
N-[1-(Adamantan-1-yl)-2-(pyridin-2-ylmethoxy)ethylidene]hy-
droxylamine (35): A solution of 28 (108 mg, 0.38 mmol) in EtOH
was treated with HONH2·HCl (53 mg, 0.76 mmol) followed by Et3N
(0.106 mL, 0.76 mmol). The mixture was refluxed with 4 ꢂ molecu-
lar sieves overnight, cooled to RT and partitioned between EtOAc
and water. The organic phase was washed with brine, dried
(MgSO4), filtered and concentrated in vacuo. Purification using
flash chromatography (CH2Cl2/CH3OH; gradient elution) gave the
product as a white solid (74 mg, 65%); mp: 102–1058C; 1H NMR
(270 MHz, CDCl3): d=1.60–1.78 (m, 6H), 1.83 (d, J=2.5 Hz, 6H),
2.00 (brs, 3H), 4.37 (s, 2H), 4.72 (s, 2H), 7.16 (m, 1H), 7.51 (d, J=
7.9 Hz, 1H), 7.68 (td, J=7.5, 1.1 Hz, 1H), 8.53 (dd, J=4.9, 0.8 Hz,
1H), 9.93 ppm (s, 1H); LC/MS (APCI): m/z: 301 [M+H]+; HRMS
(FAB): m/z [M+H]+ calcd for C18H25N2O2: 301.1916, found:
301.1929; HPLC: tR =2.1 min (98%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfonyl]ethan-1-one
(43): A white solid (22%); mp: 116–1178C; 1H NMR (270 MHz,
CDCl3): d=1.64–1.78 (m, 6H), 1.83 (d, J=2.7 Hz, 6H), 2.07 (brs,
3H), 4.26 (s, 2H), 4.70 (s, 2H), 7.28 (ddd, J=7.7, 4.9, 1.2 Hz, 1H),
7.42 (d, J=7.7 Hz, 1H), 7.72 (td, J=7.6, 2.0 Hz, 1H), 8.59 ppm (dq,
J=4.9, 0.8 Hz, 1H); LC/MS (ESI): m/z: 332 [MꢀH]+; HRMS (ESI): m/z
[M+H]+ calcd for C18H24NO3S: 334.1477, found: 334.1470; HPLC:
tR =2.1 min (>99%) in 10% H2O/CH3CN.
N-[1-(Adamantan-1-yl)-2-(pyridin-3-ylmethoxy)ethylidene]hy-
droxylamine (36): Prepared using the same method as for 35. A
white solid (85 mg, 81%); mp: 115–1178C; 1H NMR (270 MHz,
CDCl3): d=1.58–1.76 (6H, m), 1.81 (6H, d, J=2.5 Hz), 2.00 (3H, br
s), 4.28 (2H, s), 4.57 (2H, s), 7.22–7.32 (1H, m), 7.71 (1H, d, J=
8.0 Hz), 8.52 (1H, br d, J=3.8 Hz), 8.59 (1H, s), 9.93 ppm (brs, 1H,
OH); LC/MS (APCI): m/z: 301 [M+H]+; HRMS (FAB): m/z [M+H]+
calcd for C18H25N2O2: 301.1916, found: 301.1926; HPLC: tR =2.5 min
(97%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfinyl]ethan-1-one
(41): A white solid (62%); mp: 116–1198C; 1H NMR (270 MHz,
CDCl3): d=1.62–1.81 (m, 12H), 2.05 (brs, 3H), 3.56 (d, J=16.0 Hz,
1H), 3.93 (d, J=16.0 Hz, 1H), 4.02 (d, J=14.0 Hz, 1H), 4.25 (d, J=
14.0 Hz, 1H), 7.32 (dd, J=7.9, 4.9 Hz, 1H), 7.69 (dt, J=7.9, 2.2 Hz,
1H), 8.49 (d, J=1.9 Hz, 1H), 8.61 ppm (dd, J=4.9, 1.7 Hz, 1H); LC/
MS (ESI): m/z: 316 [MꢀH]+; HRMS (ESI): m/z [M+H]+ calcd for
C18H24NO2S: 318.1528, found: 318.1514; HPLC: tR =1.8 min (>99%)
in 10% H2O/CH3CN.
Method F: Synthesis of the adamantyl ethanone sulfanyl deriva-
tives 37–39: A solution of pyridinylmethyl carbamimidothioate di-
hydrochloride (480 mg, 2.0 mmol) in water (10 mL) was treated
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfonyl]ethan-1-one
(44): A white solid (21%); mp: 150–1518C; 1H NMR (270 MHz,
1626
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
CDCl3): d=1.63–1.73 (m, 6H), 1.79 (d, J=2.7 Hz, 6H), 2.08 (brs,
3H), 3.89 (s, 2H), 4.54 (s, 2H), 7.34 (dd, J=7.9, 5.0 Hz, 1H), 7.85 (dt,
J=7.9, 1.7 Hz, 1H), 8.63 (dd, J=5.0, 1.7 Hz, 1H), 8.68 ppm (d, J=
2.0 Hz, 1H); LC/MS (ESI): m/z: 334 [M+H]+; HRMS (ESI): m/z [M+
H]+ calcd for C18H24NO3S: 334.1477, found: 334.1475; HPLC: tR =
1.9 min (>99%) in 10% H2O/CH3CN.
(270 MHz, CDCl3): d=1.63–1.81 (m, 6H), 2.03 (d, J=2.7 Hz, 6H),
2.04 (brs, 3H), 3.19 (s, 2H), 3.68 (s, 2H), 7.26 (d, J=8.3 Hz, 1H),
7.68 (dd, J=8.3, 2.5 Hz, 1H), 8.31 ppm (d, J=2.5 Hz, 1H); LC/MS
(ESI): m/z: 334 [MꢀH]+; HRMS (ESI): m/z [M+H]+ calcd for
C18H23ClNOS: 336.1189, found: 336.1171; HPLC: tR =4.1 min (97%)
in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfinyl]ethan-1-one
(42): A white solid (49%); mp: 127–1298C; 1H NMR (270 MHz,
CDCl3): d=1.62–1.76 (m, 12H), 2.05 (brs, 3H), 3.57 (d, J=16 Hz,
1H), 3.96 (d, J=16 Hz, 1H), 4.00 (d, J=14 Hz, 1H), 4.24 (d, J=
13 Hz, 1H), 7.24 (dd, J=4.5, 1.6 Hz, 2H), 8.63 ppm (dd, J=4.4,
1.6 Hz, 2H); LC/MS (ESI): m/z: 318 [M+H]+; HRMS (FAB): m/z [M+
H]+ calcd for C18H24NO2S: 318.1528, found: 318.1510; HPLC: tR =
1.9 min (>99%) in 10% H2O/CH3CN.
Compounds 50–53 were synthesized using Method C:
1-(Adamantan-1-yl)-2-{[(6-chloropyridin-3-yl)methane]sulfinyl}e-
than-1-one (50): A white solid (48%); mp: 153–1548C; 1H NMR
(270 MHz, CDCl3): d=1.63–1.77 (m, 12H), 2.07 (brs, 3H), 3.55 (d,
J=16.0 Hz, 1H), 3.96 (d, J=16.0 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H),
4.24 (d, J=14.0 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.68 (dd, J=8.2,
2.5 Hz, 1H), 8.27 ppm (d, J=2.4 Hz, 1H); LC/MS (ESI): m/z: 350
[MꢀH]+; HRMS (ESI): m/z [M+Na]+ calcd for C18H22ClNO2SNa:
374.0957, found: 374.0946; HPLC: tR =1.5 min (>99%) in 10%
H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(pyridin-2-ylmethyl)sulfonyl]ethan-1-one
(45): A white solid (26%); mp: 119–1238C; 1H NMR (270 MHz,
CDCl3): d=1.62–1.78 (m, 12H), 2.07 (brs, 3H), 3.88 (s, 2H), 4.51 (s,
2H), 7.42 (dd, J=4.4, 1.3 Hz, 2H), 8.64 ppm (dd, J=4.4, 1.3 Hz, 2H);
LC/MS (ESI): m/z: 334 [M+H]+; HRMS (ESI): m/z [M+H]+ calcd for
C18H24NO3S: 334.1477, found: 334.1443; HPLC: tR =2.0 min (98%) in
10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[(6-chloropyridin-3-yl)methane]sulfonyl}e-
than-1-one (53): A white solid (24%); mp: 159–1618C; 1H NMR
(270 MHz, CDCl3): d=1.62–1.78 (m, 6H), 1.79 (d, J=2.7 Hz, 6H),
2.08 (brs, 3H), 3.90 (s, 2H), 4.52 (s, 2H), 7.38 (d, J=8.3 Hz, 1H),
7.82 (dd, J=8.3, 2.5 Hz, 1H), 8.47 ppm (d, J=2.5 Hz, 1H); LC/MS
(ESI): m/z: 366 [MꢀH]+; HRMS (ESI): m/z [M+Na]+ calcd for
C18H22ClNO3SNa: 390.0907, found: 390.0886; HPLC: tR =1.0 min
(97%) in 10% H2O/CH3CN.
2-(Acetylsulfanyl)-1-(adamantan-1-yl)ethan-1-one (46): A solution
of 5 (514 mg, 2.0 mmol) in CH3CN (25 mL) was treated with potas-
sium thioacetate (251 mg, 2.2 mmol) and stirred at RT overnight.
The reaction was diluted with water and extracted with EtOAc (3ꢁ
30 mL). The organic phase was washed with brine, dried (MgSO4),
filtered and concentrated in vacuo to give the desired product as
1-(Adamantan-1-yl)-2-{[(5-methoxypyridin-3-yl)methane]sulfony-
l}ethan-1-one (51): A white solid (51%); mp: 152–1548C; H NMR
1
(270 MHz, CDCl3): d=1.60–1.78 (m, 6H), 1.78 (d, J=2.8 Hz, 6H),
2.07 (brs, 3H), 3.59 (s, 2H), 3.87 (s, 3H), 3.92 (s, 2H), 7.35 (s, 1H),
8.25 (s, 1H), 8.36 ppm (d. J=2.5 Hz, 1H); LC/MS (APCI): m/z: 364
[M+H]+; HRMS (FAB): m/z [M+H]+ calcd for C19H26NO4S:
364.1583, found: 364.1571; HPLC: tR =2.0 min (97%) in 10% H2O/
CH3CN.
1
an off-white semi-solid (468 mg, 93%); H NMR (270 MHz, CDCl3):
d=1.66–1.88 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.32 (brs, 3H), 2.35
(s, 3H), 3.92 ppm (s, 2H); LC/MS (ESI): m/z: 253 [M+H]+; HRMS
(ESI): m/z [M+H]+ calcd for C14H21O2S: 253.1262, found: 253.1271;
HPLC: tR =2.5 min (95%) in 10% H2O/CH3CN.
Method G: Synthesis of the adamantyl ethanone sulfanyl deriva-
tives 47–49: A solution of 46 (1.0 equiv) in acetone (5 mL) was
treated with 1n NaOH (1.0 equiv) and stirred at RT under N2 for
1 h. The reaction was then treated with a solution of correspond-
ing chloromethylpyridine (1.0 equiv) in CH3CN/Et3N (4 mL/2 mL),
and the mixture was stirred at RT for overnight. The reaction was
partitioned between EtOAc and water, and the organic phase was
washed brine, dried (MgSO4), filtered and concentrated in vacuo.
Purification using flash chromatography (EtOAc/hexane; gradient
elution) gave the desired compound.
1-(Adamantan-1-yl)-2-({[6-(trifluoromethyl)pyridin-3-yl]methyl}-
sulfonyl)ethan-1-one (52): A white solid (28%); mp: 87–898C;
1H NMR (270 MHz, CDCl3): d=1.76–1.60 (m, 6H), 1.79 (d, J=2.7 Hz,
6H), 2.08 (brs, 3H), 3.93 (s, 2H), 4.07 (s, 2H), 7.72 (d, J=8.2 Hz,
1H), 8.04 (dd, J=7.7, 1.7 Hz, 1H), 8.80 ppm (brs,1H); LC/MS (ESI):
m/z: 400 [MꢀH]+; HRMS (ESI): m/z [M+H]+ calcd for C19H23F3NO3S:
402.1351, found: 402.1365; HPLC: tR =2.1 min (97%) in 10% H2O/
CH3CN.
1-(Adamantan-1-yl)-2-azidoethan-1-one (54): A cold solution of 5
(2.57 g, 10 mmol) in acetone (20 mL) was treated with NaN3
(780 mg, 12 mmol), and the mixture was stirred at 08C for 1 h and
then at RT overnight. The reaction was then partitioned between
EtOAc and water, and the organic phase was washed with brine,
dried (MgSO4), filtered and concentrated in vacuo to give an off-
1-(Adamantan-1-yl)-2-{[(5-methoxypyridin-3-yl)methyl]sulfan-
1
yl}ethan-1-one (47): A clear oil (53%); H NMR (270 MHz, CDCl3):
d=1.60–1.79 (m, 6H), 1.80 (d, J=2.5 Hz, 6H), 2.03 (brs, 3H), 3.23
(s, 2H), 3.70 (s, 2H), 3.85 (s, 3H), 7.21 (brs, 1H), 8.12 (s, 1H),
8.19 ppm (brd, J=2.5 Hz, 1H); LC/MS (ESI): m/z: 332 [M+H]+;
HRMS (ESI): m/z [M+H]+ calcd for C19H26NO2S: 332.1684, found:
332.1677; HPLC: tR =2.6 min (97%) in 10% H2O/CH3CN.
1
white semi-solid (2.0 g, 91%); H NMR (270 MHz, CDCl3): d=1.65–
1.77 (m, 6H), 1.81 (d, J=2.8 Hz, 6H), 2.04 (brs, 3H), 4.04 ppm (s,
2H); LC/MS (ESI): m/z: 242 [M+Na]+; HRMS (ESI): m/z [M+Na]+
calcd for C12H17N3NaO: 242.1269, found: 242.1257; HPLC: tR =
2.7 min (98%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-({[6-(trifluoromethyl)pyridin-3-yl]methyl}-
sulfanyl)ethan-1-one (48): A white solid (27%); mp: 80–828C;
1H NMR (270 MHz, CDCl3): d=1.58–1.80 (m, 6H), 1.80 (d, J=2.7 Hz,
6H), 2.02 (brs, 3H), 3.18 (s, 2H), 3.76 (s, 2H), 7.62 (d, J=8.0 Hz,
1H), 7.88 (dd, J=1.4, 8.0 Hz, 1H), 8.65 ppm (brs,1H); LC/MS (ESI):
m/z: 368 [MꢀH]+; HRMS (ESI): m/z [M+H]+ calcd for C19H23F3NOS:
370.1452, found: 370.1436; HPLC: tR =3.4 min (98%) in 10% H2O/
CH3CN.
1-(Adamantan-1-yl)-2-aminoethan-1-one hydrochloride (55): A
solution of 54 (1.9 g, 8.66 mmol) in CH3OH (80 mL) was treated
with HCl (36%, 1.8 mL), and the mixture was hydrogenated over
5% Pd/C (300 mg) at atmospheric pressure for 6 h. The reaction
was filtered through Celite and concentrated in vacuo. The white
crystals obtained were filtered, washed with Et2O, and dried in
vacuo (1.9 g, 95%); 1H NMR (270 MHz, [D6]DMSO): d=1.65–1.76
(m, 6H), 1.79 (d, J=2.8 Hz, 6H), 2.00 (brs, 3H), 4.03 (s, 2H),
8.11 ppm (brs, 2H); LC/MS (ESI): m/z: 194 [M+H]+ (free base).
1-(Adamantan-1-yl)-2-{[(6-chloropyridin-3-yl)methyl]sulfanyl}e-
than-1-one (49): An off-white solid (33%); mp: 88–90 C; 1H NMR
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1627

B. V. L. Potter et al.
MED
Method H: Synthesis of the amide linker derivatives 56–61: A
solution of the corresponding pyridyl carboxylic acid or pyridyl
acetic acid (1.0 equiv) in CH2Cl2 (5 mL) was treated with EDCI
(1.2 equiv), HOBt (0.5 equiv), Et3N (2.5 equiv) and DMAP (catalytic
amount) at RT. The mixture was stirred at RT for 30 min, and then
compound 55 (1.2 equiv) was added, and the reaction was stirred
overnight at RT. The mixture was partitioned between water and
CH2Cl2, and the organic phase was washed with brine, dried
(MgSO4), filtered and concentrated in vacuo. The crude product
was purified using flash chromatography with EtOAc/CH2Cl2 gradi-
ent elution.
(482 mg, 100%); mp: 160–1638C; 1H NMR (270 MHz, [D6]DMSO):
d=1.57–1.82 (m, 12H), 2.05 (brs, 3H), 4.10 (s, 2H), 4.33 (s, 2H),
7.38 (brd, J=6.9 Hz, 1H), 7.82 ( br d, J=7.2 Hz, 1H), 8.78 ppm (m,
2H); LC/MS (ESI): m/z 286 [M+H]+ (free base); HRMS (ESI): m/z
[M+H]+ (free base) calcd for C18H24NO2: 286.1807, found:
286.1796; HPLC: tR =2.1 min (>99%) in 10% H2O/CH3CN.
Acknowledgements
This work was supported by Sterix Ltd (UK), a member of the
Ipsen Group, and by the UK Wellcome Trust (Programme Grant:
082837 and VIP funding). We thank Ms. Alison. C. Smith for tech-
nical assistance, and Nicole Muller and Isabelle Viossat for CYP
inhibition and metabolic stability studies. We also thank the
ESPRC National Mass Spectrometry Service Centre (University of
Wales, Swansea, UK) for performing some high-resolution accu-
rate mass measurements.
N-[2-(Adamantan-1-yl)-2-oxoethyl]pyridine-2-carboxamide (56):
A white solid (81%); mp: 135–1368C; 1H NMR (270 MHz, CDCl3):
d=1.65–1.82 (m, 6H), 1.89 (d, J=2.7 Hz, 6H), 2.06 (brs, 3H), 4.43
(d, J=4.7 Hz, 2H), 7.41 (ddd, J=7.4, 4.1, 1.1 Hz, 1H), 7.82 (td, J=
7.4, 1.5 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.58 (dt, J=4.6, 1.0 Hz, 1H),
8.70 ppm (brs, 1H); LC/MS (ESI): m/z: 299 [M+H]+; HRMS (ESI): m/
z [M+H]+ calcd for C18H23N2O2: 299.1760, found: 299.1741; HPLC:
tR =2.3 min (99%) in 10% H2O/CH3CN.
N-[2-(Adamantan-1-yl)-2-oxoethyl]-6-methylpyridine-2-carboxa-
mide (57):
A
white solid (76%); mp: 110–1118C; 1H NMR
Keywords: 11b-HSD1 · adamantyl ethanones · diabetics ·
(270 MHz, CDCl3): d=1.65–1.80 (m, 6H), 1.90 (d, J=2.6 Hz, 6H),
2.07 (brs, 3H), 2.57 (s, 3H), 4.43 (d, J=4.7 Hz, 2H), 7.26 (d, J=
7.8 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H),
8.74 ppm (brs, 1H); LC/MS (ESI): m/z: 313 [M+H]+; HRMS (ESI): m/
z [M+H]+ calcd for C19H25N2O2: 313.1916, found: 313.1898; HPLC:
tR =2.9 min (98%) in 10% H2O/CH3CN.
hydroxysteroid dehydrogenases
syndrome
·
inhibitors
·
metabolic
[1] S. M. Grundy, H. B. Brewer, Jr., J. I. Cleeman, S. C. Smith, Jr., C. Lenfant,
Arterioscler. Thromb. Vasc. Biol. 2004, 24, e13–18.
N-[2-(Adamantan-1-yl)-2-oxoethyl]pyridine-3-carboxamide (58):
A white solid (87%); mp: 114–1158C; 1H NMR (270 MHz, CDCl3):
d=1.65–1.82 (m, 6H), 1.88 (d, J=2.7 Hz, 6H), 2.08 (brs, 3H), 4.43
(d, J=4.6 Hz, 2H), 7.06 (brs, 1H), 7.38 (dd, J=8.0, 4.7 Hz, 1H), 8.11
(dt, J=8.0, 2.2 Hz, 1H), 8.73 (dd, J=5.0, 1.8 Hz, 1H), 9.03 ppm (d,
J=2.2 Hz, 1H); LC/MS (ESI): m/z: 299 [M+H]+; HRMS (ESI): m/z
[M+H]+ calcd for C18H23N2O2: 299.1760, found: 299.1769; HPLC:
tR =1.8 min (99%) in 10% H2O/CH3CN.
[2] P. W. Wilson, R. B. D’Agostino, H. Parise, L. Sullivan, J. B. Meigs, Circula-
tion 2005, 112, 3066–3072.
[3] T. C. Sandeep, B. R. Walker, Trends Endocrinol. Metab. 2001, 12, 446–453.
[4] J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S.
Cooper, M. Hewison, P. M. Stewart, Endocr. Rev. 2004, 25, 831–866.
[5] K. E. Chapman, A. Coutinho, M. Gray, J. S. Gilmour, J. S. Savill, J. R. Seckl,
Ann. N. Y. Acad. Sci. 2006, 1088, 265–273.
[6] B. R. Walker, Diabetic Med. 2006, 23, 1281–1288.
[7] R. Thieringer, A. Hermanowski-Vosatka, Expert Rev. Cardiovasc. Ther.
2005, 3, 911–924.
N-[2-(Adamantan-1-yl)-2-oxoethyl]pyridine-4-carboxamide (59):
A white solid (59%); mp: 147–1498C; 1H NMR (270 MHz, CDCl3):
d=1.69–1.82 (m, 6H), 1.87 (d, J=2.7 Hz, 6H), 2.08 (brs, 3H), 4.42
(d, J=4.1 Hz, 2H), 7.12 (brs, 1H), 7.63 (dd, J=4.4, 1.6 Hz, 2H),
8.75 ppm (dd, J=4.4, 1.6 Hz, 2H); LC/MS (ESI): m/z: 299 [M+H]+;
HRMS (ESI): m/z [M+H]+ calcd for C18H23N2O2: 299.1760, found:
299.1742; HPLC: tR =1.9 min (99%) in 10% H2O/CH3CN.
[8] R. M. Sapolsky, L. M. Romero, A. U. Munck, Endocr. Rev. 2000, 21, 55–89.
[9] J. E. Friedman, J. S. Yun, Y. M. Patel, M. M. McGrane, R. W. Hanson, J. Biol.
Chem. 1993, 268, 12952–12957.
[10] M. Wang, Nutr. Metab. 2005, 2, 3.
[11] P. O. Hasselgren, Curr. Opin. Clin. Nutr. Metab. Care 1999, 2, 201–205.
[12] M. Wamil, J. R. Seckl, Drug Discovery Today 2007, 12, 504–520.
[13] G. Arnaldi, A. Angeli, A. B. Atkinson, X. Bertagna, F. Cavagnini, G. P.
Chrousos, G. A. Fava, J. W. Findling, R. C. Gaillard, A. B. Grossman, B.
Kola, A. Lacroix, T. Mancini, F. Mantero, J. Newell-Price, L. K. Nieman, N.
Sonino, M. L. Vance, A. Giustina, M. Boscaro, J. Clin. Endocrinol. Metab.
2003, 88, 5593–5602.
[14] B. S. McEwen, J. Clin. Endocrinol. Metab. 2002, 87, 1947–1948.
[15] A. Faggiano, R. Pivonello, S. Spiezia, M. C. De Martino, M. Filippella, C.
Di Somma, G. Lombardi, A. Colao, J. Clin. Endocrinol. Metab. 2003, 88,
2527–2533.
[16] J. W. Chu, D. F. Matthias, J. Belanoff, A. Schatzberg, A. R. Hoffman, D.
Feldman, J. Clin. Endocrinol. Metab. 2001, 86, 3568–3573.
[17] R. Fraser, M. C. Ingram, N. H. Anderson, C. Morrison, E. Davies, J. M. C.
Connell, Hypertension 1999, 33, 1364–1368.
[18] J. R. Seckl, B. R. Walker, Endocrinology 2001, 142, 1371–1376.
[19] R. C. Wilson, M. D. Harbison, Z. S. Krozowski, J. W. Funder, C. H. Shackle-
ton, H. M. Hanauske-Abel, J. Q. Wei, J. Hertecant, A. Moran, R. E. Nei-
berger, et al., J. Clin. Endocrinol. Metab. 1995, 80, 3145–3150.
[20] P. M. Stewart, A. M. Wallace, R. Valentino, D. Burt, C. H. L. Shackleton,
C. R. W. Edwards, Lancet 1987, 330, 821–824.
N-[2-(Adamantan-1-yl)-2-oxoethyl]-2-(pyridin-2-yl)acetamide
(60): A white solid (57%); mp: 137–1398C; 1H NMR (270 MHz,
CDCl3): d=1.62–1.82 (m, 12H), 2.02 (brs, 3H), 3.76 (s, 2H), 4.23 (d,
J=4.1 Hz, 2H), 7.16–7.28 (m, 2H), 7.63 (td, J=7.7, 1.6 Hz, 1H), 7.85
(brs, 1H), 8.61 ppm (m, 1H); LC/MS (ESI): m/z: 313 [M+H]+; HRMS
(ESI): m/z [M+H]+ calcd for C19H25N2O2: 313.1916, found: 313.1906;
HPLC: tR =2.0 min (98%) in 10% H2O/CH3CN.
N-[2-(Adamantan-1-yl)-2-oxoethyl]-2-(pyridin-3-yl)acetamide
(61): A white solid (53%); mp: 115–1178C; 1H NMR (270 MHz,
CDCl3): d=1.61–1.82 (m, 12H), 2.03 (brs, 3H), 3.76 (s, 2H), 4.21 (d,
J=4.1 Hz, 2H), 6.33 (brs, 1H), 7.25 (dd, J=7.9, 4.9 Hz, 1H), 7.65 (dt,
J=6.1, 1.7 Hz, 1H), 8.51 ppm (m, 2H); LC/MS (ESI): m/z: 313 [M+
H]+; HRMS (ESI): m/z [M+H]+ calcd for C19H25N2O2: 313.1916,
found: 313.1913; HPLC: tR =1.7 min (98%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(pyridin-3-ylmethoxy)ethan-1-one hydro-
chloride (62): A solution of 31 (428 mg, 1.5 mmol) in CH2Cl2 (1 mL)
was treated with HCl (3m in CH3OH, 2 mL, 6.0 mmol). The white
solid was collected and washed with Et2O, and dried in vacuo
[21] A. K. Agarwal, T. Mune, C. Monder, P. C. White, J. Biol. Chem. 1994, 269,
25959–25962.
[22] H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R.
Seckl, J. S. Flier, Science 2001, 294, 2166–2170.
1628
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1616 – 1629

Adamantyl-Derived Inhibitors of 11b-HSD1
[23] H. Masuzaki, H. Yamamoto, C. J. Kenyon, J. K. Elmquist, N. M. Morton,
J. M. Paterson, H. Shinyama, M. G. Sharp, S. Fleming, J. J. Mullins, J. R.
Seckl, J. S. Flier, J. Clin. Invest. 2003, 112, 83–90.
[24] Y. Kotelevtsev, M. C. Holmes, A. Burchell, P. M. Houston, D. Schmoll, P. Ja-
mieson, R. Best, R. Brown, C. R. W. Edwards, J. R. Seckl, J. J. Mullins, Proc.
Natl. Acad. Sci. USA 1997, 94, 14924–14929.
[25] N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C.
Fievet, B. R. Walker, J. S. Flier, J. J. Mullins, J. R. Seckl, Diabetes 2004, 53,
931–938.
[26] E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, J. S. Flier,
Diabetes 2005, 54, 1023–1031.
[27] P. Alberts, L. Engblom, N. Edling, M. Forsgren, G. Klingstrom, C. Larsson,
Y. Ronquist-Nii, B. Ohman, L. Abrahmsen, Diabetologia 2002, 45, 1528–
1532.
[28] P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norl-
ing, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M.
Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L. B. Abrahmsen, Endocri-
nology 2003, 144, 4755–4762.
[29] A. Hermanowski-Vosatka, J. M. Balkovec, K. Cheng, H. Y. Chen, M. Her-
nandez, G. C. Koo, C. B. Le Grand, Z. H. Li, J. M. Metzger, S. S. Mundt, H.
Noonan, C. N. Nunes, S. H. Olson, B. Pikounis, N. Ren, N. Robertson, J. M.
Schaeffer, K. Shah, M. S. Springer, A. M. Strack, M. Strowski, K. Wu, T. J.
Wu, J. Y. Xiao, B. B. Zhang, S. D. Wright, R. Thieringer, J. Exp. Med. 2005,
202, 517–527.
[35] C. Fotsch, M. H. Wang, J. Med. Chem. 2008, 51, 4851–4857.
[36] C. D. Boyle, T. J. Kowalski, Expert Opin. Ther. Pat. 2009, 19, 801–825.
[37] R. Ge, Y. Huang, G. Liang, X. Li, Curr. Med. Chem. 2010, 17, 412–422.
[38] R. Courtney, P. M. Stewart, M. Toh, M. N. Ndongo, R. A. Calle, B. Hirsh-
berg, J. Clin. Endocrinol. Metab. 2008, 93, 550–556.
[39] M. Hawkins, D. Hunter, P. Kishore, S. Schwartz, M. Hompesch, G. Hollis,
R. Levy, B. Williams, R. Huber, Diabetes 2008, 57 (Suppl. 1), A99–A100.
[40] J. Rosenstock, S. Banarer, V. A. Fonseca, S. E. Inzucchi, W. Sun, W. Yao, G.
Hollis, R. Flores, R. Levy, W. V. Williams, J. R. Seckl, R. Huber, Diabetes
Care 2010, 33, 1516–1522.
[41] X. Su, F. Pradaux-Caggiano, M. P. Thomas, M. W. Szeto, H. A. Halem,
M. D. Culler, N. Vicker, B. V. L. Potter, ChemMedChem 2010, 5, 1026–
1044.
[42] X. Su, N. Vicker, M. P. Thomas, F. Pradaux-Caggiano, H. A. Halem, M. D.
Culler, B. V. L. Potter, ChemMedChem, 2011, in press; DOI: 10.1002/
cmdc.201100144.
[43] M. P. Thomas, B. V. L. Potter, Future Med. Chem. 2011, 3, 367–390.
[44] R. S. Obach, Drug Metab. Dispos. 1999, 27, 1350–1359.
[45] B. Sorensen, M. Winn, J. Rohde, Q. Shuai, J. Wang, S. Fung, K. Monzon,
W. Chiou, D. Stolarik, H. Imade, L. Pan, X. Deng, L. Chovan, K. Longe-
necker, R. Judge, W. Qin, M. Brune, H. Camp, E. U. Frevert, P. Jacobson,
J. T. Link, Bioorg. Med. Chem. Lett. 2007, 17, 527–532.
[46] N. Vicker, X. Su, F. Pradaux, M. J. Reed, B. V. L. Potter, (Sterix Limited, UK),
PCT application: WO/2006/100502, 2006.
[30] B. R. Walker, A. A. Connacher, R. M. Lindsay, D. J. Webb, C. R. W. Edwards,
J. Clin. Endocrinol. Metab. 1995, 80, 3155–3159.
[47] A. Odermatt, P. Arnold, A. Stauffer, B. M. Frey, F. J. Frey, J. Biol. Chem.
1999, 274, 28762–28770.
[31] R. C. Andrews, O. Rooyackers, B. R. Walker, J. Clin. Endocrinol. Metab.
2003, 88, 285–291.
[32] X. Su, N. Vicker, B. V. L. Potter, Prog. Med. Chem. 2008, 46, 29–130.
[33] C. G. Schnackenberg, Curr. Opin. Invest. Drugs 2008, 9, 295–300.
[34] K. A. Hughes, S. P. Webster, B. R. Walker, Expert Opin. Invest. Drugs 2008,
17, 481–496.
Received: April 8, 2011
Published online on June 28, 2011
ChemMedChem 2011, 6, 1616 – 1629
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1629