Discovery of Adamantyl Heterocyclic Ketones as Potent 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors

Article abstract of DOI:10.1002/cmdc.201100144

11β-Hydroxysteroid dehydrogenase type1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

Full text of DOI:10.1002/cmdc.201100144

DOI: 10.1002/cmdc.201100144
Discovery of Adamantyl Heterocyclic Ketones as Potent
11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
Xiangdong Su,[a] Nigel Vicker,[a] Mark P. Thomas,[a] Fabienne Pradaux-Caggiano,[a]
Heather Halem,[b] Michael D. Culler,[b] and Barry V. L. Potter*[a]
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) plays a
key role in converting intracellular cortisone to physiologically
active cortisol, which is implicated in the development of sev-
eral phenotypes of metabolic syndrome. Inhibition of 11b-
HSD1 activity with selective inhibitors has beneficial effects on
various conditions, including diabetes, dyslipidemia and obesi-
ty, and therefore constitutes a promising strategy to discover
novel therapies for metabolic and cardiovascular diseases. A
series of novel adamantyl heterocyclic ketones provides potent
and selective inhibitors of human 11b-HSD1. Lead compounds
display low nanomolar inhibition against human and mouse
11b-HSD1 and are selective with no activity against 11b-HSD2
and 17b-HSD1. Selected potent 11b-HSD1 inhibitors show
moderate metabolic stability upon incubation with human
liver microsomes and weak inhibition of human CYP450 en-
zymes.
Introduction
11b-hydroxysteroid dehydrogenase isozymes (11b-HSDs) are
microsomal enzymes from the short-chain dehydrogenase/re-
ductase family that catalyse the intracellular conversion of
physiologically active glucocorticoids and their inert 11-keto
counterparts in specific tissues.[1,2] The 11b-hydroxysteroid de-
hydrogenase type 1 (11b-HSD1), highly expressed in liver, adi-
pose tissue and the central nervous system, acts as an NADPH-
dependent reductase converting cortisone (1) in humans to
the active glucocorticoid cortisol (2) (Scheme 1). The pre-recep-
tor activation of cortisone mediated by 11b-HSD1 provides a
plays essential roles in the regulation of carbohydrate, lipid
and bone metabolism, modulation of inflammatory responses,
brain function, and stress. Recent investigations have shown
that excessive glucocorticoid action is, in many respects, asso-
ciated with insulin and leptin resistance, leading to the devel-
opment of type 2 diabetes, obesity and other metabolic and
cardiovascular disorders, the major underlying causes of meta-
bolic syndrome.[7–10] Glucocorticoid receptor (GR) activation
stimulates hepatic glucose production, antagonises insulin se-
cretion from pancreatic b-cells and insulin-mediated glucose
uptake in peripheral tissues.[11–14] GR activation also promotes
lipolysis and fatty acid mobilisation.[15]
In many aspects, metabolic syndrome shares similar charac-
teristics with symptoms of Cushing’s syndrome, a systemic glu-
cocorticoid excess condition, characterised by insulin resist-
ance, high adiposity, dyslipidemia, and hypertension.[16] These
metabolic abnormities in Cushing’s syndrome can be improved
to a certain degree by reducing the excessive glucocorticoid
action through surgery or glucocorticoid receptor antagonist
treatment.[17–19] The similarities observed between phenotypes
of Cushing’s syndrome and metabolic syndrome suggest the
possibility of treating the individual indications of metabolic
syndrome by glucocorticoid activity suppression.[20] GR signal-
Scheme 1. Interconversion of glucocorticoid hormones catalysed by 11b-
HSDs.
mechanism for specific tissues to produce intracellular, nona-
drenal cortisol, thereby locally intensifying the glucocorticoid
action.[3] Conversely, the 11b-HSD2 isoform is exclusively NAD+
dependent and mainly expressed in mineralocorticoid target
tissues, such as the kidney and colon. The 11b-HSD2 isoform
catalyses the transformation of cortisol to inactive cortisone
and reduces the local concentration of cortisol in specific tis-
sues. This mechanism prevents cortisol occupation of mineralo-
corticoid receptors in the kidney, which may result in sodium
retention, hypokalaemia and hypertension.[4–6]
[a] Dr. X. Su, Dr. N. Vicker, Dr. M. P. Thomas, Dr. F. Pradaux-Caggiano,
Prof. B. V. L. Potter
Medicinal Chemistry, Department of Pharmacy and Pharmacology
University of Bath, Claverton Down, Bath BA2 7AY (UK)
Fax: (+44)1225-386-114
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 Condi-
tions set out at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-
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The tissue-specific regulation of glucocorticoid by 11b-HSDs
is of particular physiological importance, as cortisol in humans
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B. V. L. Potter et al.
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ling depends not only on the circulating glucocorticoid levels,
but also on the pre-receptor activation of glucocorticoid
within cells. Since systemic glucocorticoid levels are generally
normal in patients with common forms of obesity or over-
weight type 2 diabetics,[21] it is speculated that the intracellular
glucocorticoid concentration, regulated by 11b-HSDs, is re-
sponsible for the metabolic abnormalities. Studies show that
11b-HSD1 expression is elevated in adipose tissue of obese
subjects suggesting the possibility of tissue-specific local glu-
cocorticoid excess.[22,23]
Figure 1. Potent inhibitors of 11b-HSD1 (3, 4) and the general structure (5)
for optimisation. For full structures, see Tables 1–6.
The correlation between 11b-HSD1 activity, obesity and dia-
betes has also been validated with genetically modified rodent
models. Transgenic mice with overexpression of 11b-HSD1 in
fat tissue specifically developed symptoms of insulin-resistant
diabetes, hyperlipidemia and visceral obesity.[24,25] In contrast,
studies with 11b-HSD1 knock-out mice demonstrated that
these animals resist stress-induced hyperglycaemia, diet-in-
duced obesity, and have decreased cholesterol and triglyceride
levels.[26] Similarly, overexpression of 11b-HSD2 in transgenic
mice also results in increased insulin sensitivity, glucose toler-
ance, and resistance to body-weight gain on a high-fat diet.[27]
11b-HSD1 activity suppression in animal models with selective
bonyl group attached to the adamantane, as illustrated by
general structure 5, were synthesised (Figure 1). These target
compounds were screened for their inhibitory activity against
human 11b-HSD1 in a HEK293 cell-based assay. Selected
potent compounds were tested for inhibitory activity against
mouse 11b-HSD1. Their selectivities over 11b-HSD2 and 17b-
HSD1 were also examined.
inhibitors was found to provide beneficial effects on various in- Results and Discussion
dications of metabolic syndrome.[28–30] Moreover, clinical studies
Chemistry
suggest that inhibition of 11b-HSD1 with carbenoxolone, a
nonselective inhibitor, increased hepatic insulin sensitivity and
decreased glucose production.[31,32]
The adamantyl derivatives with an ethanone ether linker (6–9)
were generated by a nucleophilic coupling reaction between
the corresponding aryl methyl alcohols and 1-adamantyl bro-
momethyl ketone under basic conditions (Scheme 2). Most of
the target compounds with a sulfur linker can be prepared by
a coupling reaction of 1-adamantyl bromomethyl ketone with
the corresponding commercially available mercaptan in the
presence of triethylamine in acetonitrile. Further oxidation of
these compounds with meta-chloroperoxybenzoic acid (m-
CPBA) at ꢀ108C to 08C generally produced both the sulfoxide
(14, 15, 30–33) and sulfone (16, 17, 34–37) derivatives
(Scheme 2), which could be separated by flash column chro-
matography.
All this evidence supports the idea of treating type 2 diabe-
tes, obesity and other metabolic abnormalities through selec-
tive inhibition of 11b-HSD1 activity with small-molecule inhibi-
tors.[33] This approach has attracted considerable interest in the
pharmaceutical industry over the last decade,[34–37] which has
led to the discovery of numerous types of potent, selective
11b-HSD1 inhibitors.[37–42] Results from a positive proof-of-con-
cept clinical study of the potent 11b-HSD1 inhibitor
INCB013739 developed by Incyte provided substantial evi-
dence that the inhibition of 11b-HSD1 can be a viable treat-
ment of type 2 diabetes. It was reported that INCB013739
treatment of type 2 diabetes mellitus patients who failed on
metformin monotherapy could significantly improve hepatic
and peripheral insulin sensitivity and reduce haemoglobin A1c
and fasting plasma glucose. In patients with hyperlipidaemia
or hypertriglyceridaemia, treatment with INCB013739 also
lowers triglyceride and cholesterol levels.[43,44]
Synthesis of the furanylmethylthio 1-adamantylethanone de-
rivative 18 was performed through a nucleophilic substitution,
followed by a coupling reaction of ethanthioate with methyl 5-
(chloromethyl)furan-2-carboxylate as illustrated in Scheme 3.
Hydrolysis of the methyl ester and subsequent amide forma-
tion gave compounds 19 and 20. Their corresponding sulfox-
ide (21, 24) and sulfone derivatives (22, 23 and 25) were syn-
thesised by oxidation with m-CPBA (Scheme 3). No sulfoxide
product was obtained from the oxidation of 19 under these
conditions.
To discover novel, clinically useful inhibitors of 11b-HSD1, it
is important to have an array of structural types of inhibitor, as
the physicochemical properties of the compounds will deter-
mine tissue distribution, hypothalamic–pituitary–adrenal axis
effects, and, ultimately, clinical utility. Previously, we reported
that some adamantyl ethanone derivatives possess high inhibi-
tory activity on the cellular 11b-HSD1 enzyme.[45] Compounds 3
and 4 exhibit potent inhibition of 11b-HSD1 with IC50 values of
approximately 60 nm. To further improve potency, pharmacoki-
netic properties and physicochemical properties, we performed
optimisation on this series of compound using structure-based
design.[46] Compounds containing an adamantyl group linked
to a heterocyclic unit through a multiatom linker with a car-
Target compounds 38–42 were synthesised from substituted
4H-1,2,4-triazole-3-thiol intermediates, which were obtained
through the cyclisation of substituted hydrazinecarbothioa-
mide under basic conditions (Scheme 4).
Most of the designed 1,3,4-thiadiazole derivatives can be
made from the commercially available substituted (1,3,4-thia-
diazol-2-yl)methanethiol via a coupling reaction with 1-ada-
mantyl bromomethyl ketone. The 5-N,N-dimethylamine substi-
tuted compound (45) was prepared by cyclisation of N,N-dime-
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11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
Scheme 5. Synthesis of 1,3,4-thiadiazole derivative (45). Reagents and condi-
tions: a) CS2, Et3N, DMF; b) 1-adamantyl bromomethyl ketone, Et3N (54%
yield).
thylhydrazinecarbothioamide with carbon disulfide, followed
by a coupling reaction as shown in Scheme 5.
Scheme 2. Synthesis of the adamantyl ethanone compounds. Reagents and
conditions: a) ArCH2OH, NaH, THF, 08C; b) ArCH2SH, Et3N, CH3CN, RT; c) m-
CPBA, CH2Cl2, ꢀ10!08C.
Structure–activity relationships (SAR)
The target compounds were examined for their inhib-
ition against 11b-HSD1 on an HEK293 cell line trans-
fected with the human HSD11B1 gene. Our previous
study found that adamantyl ethanone derivatives ex-
hibited 11b-HSD1 inhibitory activity with lead com-
pounds showing IC50 values in the range of 50–
60 nm.[45] Compounds 3 and 4, with a substituted
benzyl or phenyl group, respectively, attached to the
adamantyl ethanone through an ether linker, demon-
strate high potency, good selectivity over 11b-HSD2,
and moderate metabolic stability in human liver mi-
crosomes.[45] Therefore, the adamantyl ethanone
moiety represents a suitable template for further op-
timisation.
Replacing the phenyl group of compound 3 with
2-thiophene generated compound 6, which shows
moderate activity (IC50 =410 nm). Moving the sulfur
to the 3-position only increases the activity slightly
(7, IC50 =280 nm). However, the introduction of a 2-
thiazole ring results in a tenfold improvement in in-
hibitory activity, generating the highly potent com-
pound 8 with an IC50 value of 41 nm. The improve-
ment in activity may be due to the added interaction
of the nitrogen atom with the protein in the binding
site or the change in molecular physicochemical
properties. When a methyl group was added to the
Scheme 3. Synthesis of furanyl adamantyl ethanone derivatives (18–25). Reagents and
conditions: a) AcSK, CH3CN, RT; b) 1. 1n NaOH, acetone; 2. methyl-5-(chloromethyl)furan-
2-carboxylate, RT; c) KOH, CH3OH, RT; d) NHMe2, EDCI, DMAP, Et3N, CH2Cl2, RT; e) m-CPBA,
CH2Cl2, ꢀ10!08C.
5-position of the thiazole ring, the activity reduces slightly (9,
Table 1).
To investigate the possible binding mode of the inhibitor,
compound 8 was docked into the published X-ray crystal
structure of 11b-HSD1 (PDB: 2ILT[47]) using the GOLD docking
program (version 4.1). The best docking solution predicts that
the adamantyl group will pack nicely between the nicotina-
mide ring of the cofactor and Y183, and the carbonyl is able to
stack with the nicotinamide amide. The thiazole ring is predict-
ed to have an edge-on interaction with Y177 (~4 ꢁ) (Figure 2).
We also evaluated the effect of replacing the oxygen linker
with a sulfur atom in the same core structure (Table 2). Com-
Scheme 4. Synthesis of 1,2,4-triazole derivatives (38–42). Reagents and condi-
tions: a) 2n NaOH; b) 1. 2n NaOH; 2. HCl, CH3OH; c) 1-adamantyl bromo-
methyl ketone, Et3N.
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Table 1. In vitro inhibition of compounds 6–9.
Table 2. In vitro inhibition of compounds 10–17.
Ar[a]
IC50[b] [nm]
410
Compd
X
S
Ar[a]
IC50[b] [nm]
Compd
10
143
6
7
11
12
S
S
163
244
280
8
9
41
71
13
S
327
[a] Point of attachment indicated by . [b] The IC values are reported as
the mean of three measurements with variance less than 20%.
14
15
16
17
SO
SO
46
41
*
50
SO2
SO2
202
36
[a] Point of attachment indicated by . [b] The IC values are reported as
*
50
the mean of three measurements with variance less than 20%.
a sulfone linker, exhibits similar potency compared with the
sulfide analogue 10, but a fourfold weaker potency compared
with the sulfoxide compound 14. However, compound 17 with
a furanyl ring maintains the same potency (IC50 =36 nm) as its
sulfoxide analogue 15. A docking study with 17 found that
there is a possible hydrogen-bond interaction from S170 to
the carbonyl and from Y183 to either the carbonyl or one of
the SO2 oxygen atoms.
Based on the positive results from the adamantyl ethanone
furanyl series, the possibility of altering the substitution on the
furan ring was explored (Table 3), as our previous work indicat-
Figure 2. Docking pose of compound 8 (cyan) with cofactor (purple) and
active site residues (green).
pared with 6, the activity of compound 10 increases by nearly
threefold with an IC50 value of 143 nm, suggesting that the
sulfur linker may enable more favourable interactions with the
protein. Similarly, compound 11 with the furan-2-yl group is
equally potent. However, this effect was not observed in com-
pounds with a thiazolyl group in the aromatic region. Com-
pounds 12 (IC50 =244 nm) and 13 (IC50 =327 nm) exhibit re-
duced activity compared to their oxygen linker countparts 8
and 9, respectively, indicating that the linker change may alter
the binding position of the thiazolyl ring. Interestingly, we
found that the change of the sulfide linker to a sulfoxide great-
ly raises the inhibitory activity to under 50 nm for both thio-
phenyl and furanyl derivatives (14, 15), suggesting that the
oxygen on the sulfur possibly forms further interactions with
the enzyme or alters the geometry of the molecule placing the
adamantyl and/or the aromatic ring in a position to gain fur-
ther binding interactions in the active site. Compound 16, with
Table 3. In vitro inhibition of compounds 18–25.
Compd
X
R
IC50[a] [nm]
18
19
20
21
22
23
24
25
S
S
S
SO
SO2
SO2
SO
SO2
COOMe
COOH
CONMe2
COOMe
COOMe
COOH
264
67%[b]
153
102
239
4%[b]
144
CONMe2
CONMe2
122
[a] The IC50 values are reported as the mean of three measurements with
variance less than 20%. [b] Percent inhibition measured at a concentra-
tion of 1 mm and reported as the mean value of three experiments with
variance <20%.
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11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
ed that a hydrogen-bonding group on the aromatic ring might
potentially improve the inhibition of 11b-HSD1.[45] Surprisingly,
the 5-methyl ester derivative 18 shows reduced activity (IC50 =
264 nm) compared with the unsubstituted compound 11
(IC50 =163 nm). Although the sulfoxide linker analogue 21 re-
gains the activity by 2.6-fold, with an IC50 value of 102 nm, it is
still less potent in comparison with the unsubstituted sulfoxide
(15, IC50 =41 nm). The sulfone-linked compound 22 exhibits
only 15% of the potency of the unsubstituted compound 17.
Two compounds (19 and 23) with a free carboxylic acid on the
5-position both gave poor activity, possibly due to their low
permeability when tested on the HEK293 cell line. Compound
20 (IC50 =153 nm), with the N,N-dimethylcarboxamide substitu-
tion, is equally potent as the unsubstituted compound 11;
however, alteration of the linker to sulfoxide or sulfone (24
and 25) does not improve the inhibitory activity in the same
way as that observed in the unsubstituted series (15 and 17).
From the above SAR data, we found that the core structure
of adamantyl ethanone linked to methyl 2-thiophenyl or
methyl 2-furanyl moieties through a sulfoxide or sulfone group
normally generates potent inhibitors of 11b-HSD1. Compounds
14, 15 and 17, with IC50 values below 50 nm, are the most
potent inhibitors from this new series (Table 2 and Table 3).
To investigate the SAR of adamantyl ethanone derivatives
with the heterocyclic ring attached directly to a sulfur linker,
we synthesised four series of compound containing different
5-membered ring systems and evaluated their inhibition
(Table 4). The thiophenyl derivative 26 (IC50 =101 nm) shows
activity similar to analogue 10, which has an extra methylene
unit between the sulfur and aromatic ring. Replacing the thio-
phene ring with 1-methyl-1H-imidazole or 5-methyl-1,3,4-thia-
diazole gave two compounds with slightly improved potency
(27: IC50 =93 nm; 29: IC50 =61 nm). Interestingly, when a 4-
methyl-4H-1,2,4-triazole moiety was introduced, the most
potent compound 28, with an IC50 value of 19 nm, was identi-
fied. The 4H-1,2,4-triazole core structure can be found in many
potent 11b-HSD1 inhibitors reported previously.[48–51] The dra-
matic increase in activity could be the result of a network of in-
teractions with the triazole ring. A docking study with com-
pound 28 found that the highest docking score solution poses
the triazole ring close to the cofactor with the triazole methyl
group fitting in a pocket formed by I121, T124 and Y183. The
carbonyl group is predicted to form hydrogen bonds to Y183
and S170 (both ~2.5 ꢁ). The adamantyl group is predicted to
fit tightly in a hydrophobic pocket formed by L171, Y177 and
L217 (Figure 3).
Table 4. In vitro activity of compounds 26–37.
Compd
X
S
Ar[a]
IC50[b] [nm]
26
101
27
28
S
S
93
19
29
30
S
61
59
SO
31
32
SO
SO
48
27
33
34
SO
26
SO2
667
35
SO2
62
36
37
SO2
SO2
95
31
[a] Point of attachment indicated by . [b] The IC values are reported as
*
50
the mean of three measurements with variance less than 20%.
The sulfone version of this series displays mixed results. The
thiophenyl derivative 34, the least potent in this series, loses
11-fold activity compared with the sulfoxide analogue 30. Simi-
larly, triazole derivative 36 (IC50 =95 nm) has an activity 3.5-fold
lower than the sulfoxide analogue 32, and fivefold lower than
the sulfide analogue 28. However, compound 37 (IC50 =31 nm)
still retains the same level of potency as the compound with a
sulfoxide linker (33, Table 4). As one of the most potent com-
pounds with a sulfone linker, this compound is of particular in-
terest for further investigation.
All compounds with a sulfoxide linker (30–33) are highly
potent. Among them, the 4H-1,2,4-triazole derivative 32 and
the 5-methyl-1,3,4-thiadiazole derivative 33 are the most
potent, with IC50 values of 27 nm and 26 nm, respectively. In
comparison with their sulfide linker analogues, compounds 30,
31 and 33 all exhibit nearly double the potency. This observa-
tion is in agreement with that seen in the previous series
(Table 2), indicating that the sulfoxide linkers may not only
change the geometry of the molecule but may also act as hy-
drogen-bond acceptors with amino acid residues in the active
site of 11b-HSD1.
Having found that the 4H-1,2,4-triazole and 5-methyl-1,3,4-
thiadiazole derivatives display significant inhibition against
11b-HSD1, we investigated the SAR for variation of substitu-
ents with different size and electronic properties on the aro-
matic ring (Tables 5 and 6). The 5-methyl substituent on the
4H-1,2,4-triazole ring gives a compound with relatively high
potency (38, IC50 =36 nm; Table 5); however, it is approximate-
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A series of 1,3,4-thiadiazole derivatives with varied substitu-
ents in the 5-position was studied for inhibitory activity
(Table 6). The methylthio- or ethylthio-substituted compounds
(46 and 47) only exhibit moderate inhibition of 11b-HSD1.
Table 6. In vitro activity of 1,3,4-thiadiazole derivatives 45–52.
Compd
X
R
IC50[b] [nm]
45
46
47
48
49
50
51
52
S
S
S
S
SO2
S
NMe2
SMe
SEt
NH2
NH2
NHAc
NHAc
NHAc
4005
306
68%[b]
71
1787
848
333
SO
SO2
Figure 3. Docking solution of compound 28 (cyan) with cofactor (purple)
and active site residues (green).
309
[a] The IC50 values are reported as the mean of three measurements with
variance less than 20%. [b] Percent inhibition measured at a concentra-
tion of 1 mm and reported as the mean value of three experiments with
variance <20%.
Table 5. In vitro activity of 1,2,4-triazole derivatives.
Compound 46, with an IC50 value of 306 nm, shows 20% of
the activity of the methyl-substituted 29. The 5-N,N-dimethyla-
mino substituent also has a strongly negative effect on the ac-
tivity (45, IC50 =4005 nm), suggesting the possibility of limited
steric and/or electronic requirements in a confined region.
It is interesting to note that the amino-substituted com-
pound (48), with an IC50 value of 71 nm, shows nearly the
same level of potency as the methyl-substituted compound
29. The benefit of having an amino group on the 1,3,4-thiadia-
zole ring is that it can provide a handle for further optimisa-
tion. A docking study suggested the possibility of the thiadia-
zole amino group of 48 forming hydrogen bonds with NADP
phosphate (3.4 ꢁ), and the carbonyl group interacting with
Y183 (2.8 ꢁ) and S170 (2.5 ꢁ) also through hydrogen bonds. It
was surprising to see the sulfone-linked analogue 49 exhibiting
only modest activity with an IC50 value of 1787 nm. The acet-
amide substituent (50, IC50 =848 nm) reduces the activity of 48
by almost 12-fold, providing further proof that the size of the
substituent is crucial to the activity. Although oxidation of the
sulfide linker of 50 to sulfoxide or sulfone raised the inhibitory
activity by about 2.5-fold, compounds 51 (IC50 =333 nm) and
52 (IC50 =309 nm) are still far less potent than their methyl-
substituted analogues 33 and 37.
Compd
R1
R2
IC50[a] [nm]
38
39
40
41
42
43
44
Me
i-propyl
Me
Me
Me
Me
Me
36
137
129
153
97
cyclopropyl
CH2OMe
CH2COOMe
cyclopropyl
2-thienyl
cyclopropyl
Me
1857
5871
[a] The IC50 values are reported as the mean of three measurements with
variance less than 20%.
ly twofold less active than the unsubstituted derivative 28.
Substitution with a hydrophobic cyclopropyl group (40, IC50 =
129 nm) results in a further decrease in activity by a further
3.6-fold, suggesting that the size of the substituent permitted
in the aromatic region could be limited. The 5-thiophenyl-sub-
stituted compound 44 exhibits very low activity with an IC50
value of 5871 nm. This dramatic loss in activity may be due to
an alteration of the binding mode caused by the biaryl unit or
the physiochemical properties of the molecule. The introduc-
tion of a group with hydrogen bonding capacity at the 5-posi-
tion keeps the IC50 value in the range of 100–150 nm (41 and
42, Table 5); however, these compounds are three- to fourfold
less active than the 5-methyl analogue 38 and much less
active than the unsubstituted compound 28. Replacement of
the methyl group of compound 38 with an iso-propyl group
leads to a 3.8-fold loss of activity (39, IC50 =137 nm), suggest-
ing that the bulkier groups are not favoured in that region.
This observation is in agreement with the result for compound
43 (IC50 =1857 nm), with cyclopropyl substituents at both the
1- and 5-positions.
Having identified ten potent compounds, with IC50 values
below 50 nm, from these adamantyl ethanone derivatives, we
examined their inhibition against mouse 11b-HSD1, since a
mouse model will most likely be used in vivo. Compounds 8,
14, 15, 33 and 37 all exhibit similar levels of potency against
the mouse and human enzymes, which makes them suitable
for further evaluation in mouse models. Although compounds
17, 28, 31 and 38 are several fold less active on the mouse
enzyme, they still show relatively strong activity, especially
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11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
compound 28 (human: IC50 =19 nm, mouse: IC50 =61 nm;
Table 7). Compounds 17, 28, 31 and 38 were also tested for
their inhibition against human 11b-HSD2 and 17b-HSD1. At a
concentration of 10 mm, these compounds are all inactive (data
not shown) and therefore are regarded as highly selective 11b-
HSD1 inhibitors.
Table 8. Metabolism studies in human liver microsomes.[a]
Compd
t1/2 [min]
CLint [mLminꢀ1 mgꢀ1
]
15
17
28
37
39
257
68
17.6
2.9
8.7
19
34
[a] The parent compound is incubated at 378C with human liver micro-
somes in presence of the cofactor NADPH for 40 min. Disappearance of
Table 7. Inhibition of human and mouse 11b-HSD1.
the parent compound is monitored using a HPLC system. Half-life (t1/2
)
and intrinsic clearance (CLint) values were calculated accordingly.[52] Data
reported as the mean value of two experiments.
Compd
IC50[a] [nm]
human
mouse
8
41
46
41
36
19
48
27
26
31
36
18
20
38
176
61
121
3084
44
14
15
17
28
31
32
33
37
38
proved metabolic stability with a half-life of more than 1 h and
an intrinsic clearance of ~9 mLminꢀ1 mgꢀ1. More interestingly,
compound 17 is relatively stable under the human liver micro-
somes incubation conditions, displaying a half-life of more
than 4 h and a clearance rate below 3 mLminꢀ1 mgꢀ1. This
clearly indicates that metabolic stability suitable for a com-
pound to be dosed in vivo may be achieved with this structur-
al template.
57
248
[a] The IC50 values are reported as the mean of three measurements with
variance less than 20%.
To examine the possibility of these compounds interfering
with the metabolism of other drugs, compounds 14, 17, 28
and 37 were tested for their inhibition of key human cyto-
chrome P450 enzymes: 1A2, 2C9, 2C19, 2D6, 3A4-BFC and
3A4-BQ (Table 9). Compound 14 shows very weak activity
To improve the solubility of an adamantyl ethanone deriva-
tive, compound 37 was transformed into the enolate sodium
salt (53) (Scheme 6), which exhibits enhanced water solubility
(>4 mgmLꢀ1) in a Na2HPO4 buffer solution with or without 5%
N,N-dimethylacetamide (DMA) as a cosolvent. Compound 53
displays relatively high potency against 11b-HSD1 with an IC50
value of 108 nm.
Table 9. Inhibition of human cytochrome P450 enzymes by selected ana-
logues.
CYP450
Compd 14
Compd 17[a]
Compd 28
Compd 37
1A2
2C9
2C19
2D6
3A4-BFC[b]
3A4-BQ[c]
33 mm
ND
30 mm
ND
>100 mm
12 mm
0
21 mm
ND
3.6 mm
ND
>100 mm
11 mm
17 mm
>100 mm
6.3 mm
52%[a]
92%[a]
0
86%[a]
52%[a]
>100 mm
62 mm
30 mm
[a] Percent inhibition measured at a concentration of 10 mm. [b] BFC=7-
benzyloxy-trifluoromethylcoumarin [c] BQ=7-hydroxy-quinoline ND: not
determined. Data reported as the mean value of two measurements.
Scheme 6. Potent compound 53 with improved solubility.
Permeability, metabolic stability and CYP450 inhibition
studies
The membrane permeability of two selected compounds (14
and 31) was determined using the Caco-2 cell model. The ap-
parent permeability coefficient (Papp) of each drug from the
apical to basolateral side was measured at a concentration of
20 mm. The results indicate that both compounds possess high
permeability (14: Papp (A>B)=2.2ꢂ10ꢀ5; 31: Papp (A>B)=4.4ꢂ
10ꢀ5), which supports the fact that these molecules are of a lip-
ophilic nature.
against 1A2, 2C19, 3A4-BFC and 3A4-BQ. Compound 28 dis-
plays moderate inhibition of 2C19, with an IC50 value of
3.6 mm, and compound 37 inhibits 3A4-BFC with an IC50 value
of 6.3 mm. Compound 17, although showing no inhibition for
1A2 and 2D6, exhibits inhibition at a concentration of 10 mm
for 2C9 (52%), 2C19 (92%), 3A4-BFC (86%) and 3A4-BQ (52%).
Conclusions
Potent inhibitors 15, 17, 28 and 37 were evaluated for their
metabolic stability in human liver microsomes (Table 8). Com-
pounds 15 and 37 both suffer from rapid metabolism under
the test conditions, with a half-life of only 30–40 min and a
high clearance rate. However, triazole derivative 28 shows im-
In summary, we have identified several new series of adaman-
tyl ethanone heterocyclic derivatives as novel inhibitors of
human and mouse 11b-HSD1. The ten most potent com-
pounds (Table 7) display selective high inhibitory activity
ChemMedChem 2011, 6, 1439 – 1451
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www.chemmedchem.org
1445

B. V. L. Potter et al.
MED
60 F254). Products were visualised by UV irradiation at 254 nm and
staining with 5% w/v molybdophosphoric acid in EtOH, followed
by heating. Flash column chromatography was performed on pre-
packed columns (RediSep Rf) and gradient elution (solvents indicat-
ed in text) on the Combiflash RF system (Teledyne Isco). 1H 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 internal standard. LC/MS spectra
were recorded on a Waters 2790 machine with Waters “Symmetry”
C18 column (packing: 3.5 mm, 4.6 mm ꢂ 75 mm) eluting with 10%
H2O/CH3OH (1 mLminꢀ1), and detected with a ZQ MicroMass spec-
trometer and photodiode array (PDA) detector using atmospheric
pressure chemical ionisation (APCI) or electrospray ionisation (ESI).
High-resolution mass spectra (HRMS) were recorded on a Bruker
MicroTOF with ESI or at the EPSRC National Mass Spectrometry ser-
vice (Swansea, UK) with FAB-MS using m-nitrobenzyl alcohol (NBA)
as the matrix. HPLC was undertaken using a Waters 717 machine
with Autosampler and PDA detector. The column used was a
Waters “Symmetry” C18 (packing: 3.5 mm, 4.6 mmꢂ150 mm) with
an isocratic mobile phase consisting of H2O/CH3CN at a flow rate
against 11b-HSD1, with IC50 values below 50 nm, when evaluat-
ed on a stably transfected HEK293 cell line. It was found that
an adamantyl ethanone motif tethered to a 5-membered aro-
matic heterocycle through an oxygen, sulfur, sulfoxide or sul-
fone linker provides a suitable pharmacophore for inhibition of
11b-HSD1. The further optimisation of the previously reported
compounds 3 and 4 lead to a potent inhibitor with approxi-
mately a threefold improvement in activity. Compound 28
(11b-HSD1, human IC50 =19 nm, mouse IC50 =61 nm) displays
reasonable metabolic stability under human liver microsomes
incubation conditions with a half-life of 68 min and very weak
inhibition of key human CYP450 enzymes. This compound, in
particular, is regarded as a candidate for further preclinical in-
vestigation.
Experimental Section
of 1.0 mLminꢀ1
.
11b-HSD1 inhibition cellular assay using a scintillation proximity
assay (SPA) protocol:[53] Wild type HEK293 cells lack endogenous
11b-HSD1 activity and this cell line has been shown to be a suita-
ble system for evaluating 11b-HSD1 activity after being transfected
with the plasmid for expression of 11b-HSD1 or 11b-HSD2. The
enzyme activity was determined by measuring the amount of triti-
ated product by 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 protocols. Cells were incubated in 96-well micro-plates in
the presence of tritiated substrate and the assay plates contained
internal high and low controls to allow calculation of percentage
inhibition. Each well of a 96-well culture plate was seeded with
HEK293/HSD11B1 cells in 100 mL medium. When the cells were
80% confluent, the medium was removed from each well then
100 mL of fresh, serum-free, medium containing [3H]cortisone and
test compound in 1% DMSO was added to each well. 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 378C for the required time period, after which, 50 mL
of media was removed from each well and transferred to a micro-
plate containing 100 mL of a pre-incubated mixture of anti-cortisol
antibody 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.
Method A: Synthesis of adamantyl ethanone ether compounds
6–9: A suspension of NaH (60% in mineral oil, 1.2 mmol) in dry
THF (4 mL) was treated with the corresponding alcohol (1.1 mmol)
at 08C. After stirring for 20 min at 08C, a solution of adamantan-1-
yl bromomethyl ketone (1.0 mmol) in dry THF (4 mL) was added.
The mixture was stirred for 2 h at 08C then at RT for 12 h. After
quenching with water (10 mL), the mixture was extracted with
Et2O (2ꢂ30 mL). The organic phase was washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (hexane/EtOAc or CH2Cl2/
EtOAc; gradient elution).
1-(Adamantan-1-yl)-2-(thiophen-2-ylmethoxy)ethanone (6): An
off-white solid (79 mg, 27%): mp: 57–588C; 1H NMR (270 MHz,
CDCl3): d=1.56–1.79 (m, 12H), 2.21 (br s, 3H), 4.30 (s, 2H), 4.75 (s,
2H), 6.98 (m, 2H), 7.30 ppm (m, 1H); LC/MS (APCI): m/z 291 [M+
H]+; HRMS-FAB: m/z [M+Na]+ calcd for C17H22O2SNa: 313.1238,
found: 313.1226; HPLC: tR =2.98 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(thiophen-3-ylmethoxy)ethanone (7):
A
1
white solid (68 mg, 23%): mp: 58–608C; H NMR (270 MHz, CDCl3):
d=1.63–1.79 (m, 6H), 1.80 (d, J=3.0 Hz, 6H), 2.01 (br s, 3H), 4.28
(s, 2H), 4.58 (s, 2H), 7.10 (dd, J=1.5, 5.0 Hz, 1H), 7.22 (m, 1H,),
7.30 ppm (1H, dd, J=3.0, 5.0 Hz); LC/MS (APCI): m/z 313 [M+Na]+;
HRMS-FAB: m/z [M+H]+ calcd for C17H23O2S: 291.1413, found:
291.1407; HPLC: tR =3.26 min (98%) in 10% H2O/CH3CN.
Docking study procedure: Selected ligands were docked into the
human 11b-HSD1 protein X-ray crystal structure (PDB: 2ILT[47]
)
using the GOLD docking program (version 4.1) with default set-
tings in the presence of the cofactor. The binding site was defined
as a sphere of 10 ꢁ 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 to
generate the best poses of the ligand in the active site.
1-(Adamantan-1-yl)-2-(1,3-thiazol-2-ylmethoxy)ethanone (8):
A
1
white solid (81 mg, 28%): mp: 89–918C; H NMR (270 MHz, CDCl3):
d=1.58–1.74 (m, 6H), 1.76 (d, J=2.8 Hz, 6H), 1.98 (br s, 3H), 4.28
(s, 2H), 4.76 (s, 2H), 7.75 (s, 1H), 8.77 ppm (s, 1H); LC/MS (APCI):
m/z 292 [M+H]+; HRMS-FAB: m/z [M+H]+ calcd for C16H22NO2S:
292.1371, found: 292.1372; HPLC: tR =2.4 min (98%) in 10% H2O/
CH3CN.
General methods for synthesis: 1-Adamantyl bromomethyl
ketone was obtained from Aldrich Chemical Co. (Gillingham, UK).
All other chemicals were purchased from either Aldrich Chemical
Co. or Alfa Aesar (Heysham, UK). All organic solvents of AR grade
were supplied by Fisher Scientific (Loughborough, UK). Melting
points were determined using a Stanford Research Systems Opti-
melt MPA100 and are uncorrected. Compounds in solid form were
crystallised from CH2Cl2/EtOAc. Thin layer chromatography (TLC)
was performed on pre-coated aluminium plates (Merck, silica gel
1-(Adamantan-1-yl)-2-[(4-methyl-1,3-thiazol-2-yl)methoxy]etha-
none (9): A white solid (165 mg, 54%): mp: 77–808C; 1H NMR
(270 MHz, CDCl3): d=1.57–1.70 (m, 6H), 1.75 (d, J=2.8 Hz, 6H),
1.96 (br s, 3H), 2.36 (s, 3H), 4.37 (s, 2H), 4.75 (s, 2H), 6.82 ppm (s,
1H); LC/MS (APCI): m/z 306 [M+H]+; HRMS-FAB: m/z [M+H]+
calcd for C17H24NO2S: 306.1528, found 306.1531; HPLC: tR =2.6 min
(97%) in 10% H2O/CH3CN.
1446
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ChemMedChem 2011, 6, 1439 – 1451

11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
Method B: Synthesis of the adamantyl ethanone sulfanyl deriva-
tives 10–13: A solution of adamantan-1-yl bromomethyl ketone
(1 equiv) in CH3CN (15 mL) was treated with the corresponding
mercaptan (1.1 equiv), followed by Et3N (3 equiv), and 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 to give the crude product, which
was purified with flash chromatography (hexane/EtOAc or CH2Cl2/
EtOAc; gradient elution).
Na]+ calcd for C17H22NaO3S2: 361.0908, found: 361.0889; HPLC: tR =
2.4 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(furan-2-ylmethanesulfinyl)ethanone (15):
A white solid (100 mg, 33%): mp: 75–798C; 1H NMR (270 MHz,
CDCl3): d=1.56–1.84 (m, 12H), 2.06 (br s, 3H), 3.67 (d, J=15 Hz,
1H), 3.93 (d, J=15 Hz, 1H), 4.20 (AB, 2H), 6.04–6.44 (m, 2H),
7.44 ppm (dd, J=1.8, 0.7 Hz, 1H); LC/MS (APCI): m/z 307 [M+H]+;
HRMS-FAB: m/z [M+Na]+ calcd for C17H22O3SNa: 329.1187, found:
329.1164; HPLC: tR =2.54 min (>99%) in 20% H2O/CH3CN. 1-(Ada-
mantan-1-yl)-2-[(furan-2-ylmethane)sulfonyl]ethanone (17): An
1-(Adamantan-1-yl)-2-(thiophen-2-ylmethylsulfanyl)ethanone
(10): A semi-solid (160 mg, 52%): 1H NMR (270 MHz, CDCl3): d=
1.62–1.81 (m, 12H), 2.02 (br s, 3H), 3.32 (s, 2H), 3.95 (s, 2H), 6.88–
6.94 (m, 2H), 7.20 ppm (dd, J=5.0, 1.3 Hz, 1H); LC/MS (ESI): m/z
307 [M+H]+; HRMS-ESI: m/z [M+Na]+ calcd for C17H22OS2Na:
329.1010, found: 329.0982; HPLC: tR =5.1 min (97%) in 20% H2O/
CH3CN.
1
off-white solid (166 mg, 52%): mp: 99–1008C; H NMR (270 MHz,
CDCl3): d=1.65–1.85 (m, 12H), 2.07 (br s, 3H), 4.02 (s, 2H), 4.61 (s,
2H), 6.40 (t, J=2.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 7.45 ppm (d, J=
2.7 Hz, 1H); LC/MS (APCI): m/z 323 [M+H]+; HRMS-FAB: m/z [M+
H]+ calcd for C17H23O4S: 323.1317, found: 323.1326; HPLC: tR =
2.0 min (>99%) in 10% H2O/CH3CN.
Methyl 5-({[2-(adamantan-1-yl)-2-oxoethyl]sulfanyl}methyl)furan-
2-carboxylate (18): A solution of 2-(acetylsulfanyl)-1-(adamantan-1-
yl)ethanone (1.76 g, 6.97 mmol) in acetone (20 mL) was treated
with 1n NaOH (7 mL). The mixture was stirred at RT under nitro-
gen for 1 h. Methyl 5-(chloromethyl)furan-2-carboxylate (1.2 g,
6.87 mmol) in CH3CN/Et3N (20–8 mL) was added. After stirring at
RT for 12 h, the mixture was partitioned between EtOAc and brine.
The organic phase was washed with brine, dried over MgSO4, fil-
tered and concentrated in vacuo. Purification with flash column
(EtOAc/petrolium ether; gradient elution) yielded a colourless oil
(1.24 g, 52%): 1H NMR (270 MHz, CDCl3): d=1.65–1.80 (m, 6H),
1.82 (d, J=2.7 Hz, 6H), 2.02 (br s, 3H), 3.36 (s, 2H), 3.75 (s, 2H),
3.86 (s, 3H), 6.34 (d, J=3.5 Hz, 1H), 7.05 ppm (d, J=3.5 Hz, 1H);
LC/MS (ESI): m/z 371 [M+Na]+; HRMS-FAB: m/z [M+Na]+ calcd for
C19H24NaO4S: 371.1293, found: 371.1255; HPLC: tR =2.86 min (98%)
in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(furan-2-ylmethylsulfanyl)-ethanone (11):
A semi-solid (180 mg, 62%): 1H NMR (270 MHz, CDCl3): d=1.69–
1.83 (m, 6H), 1.82 (d, J=2.2 Hz, 6H), 2.03 (br s, 3H), 3.33 (s, 2H),
3.75 (s, 2H), 6.18–6.20 (m, 1H), 6.29 (dd, J=3.1, 1.7 Hz, 1H),
7.35 ppm (dd, J=2.0, 1.0 Hz, 1H); LC/MS (ESI): m/z 291 [M+H]+;
HRMS-ESI: m/z [M+Na]+ calcd for C17H22O2SNa: 313.1238, found:
313.1221; HPLC: tR =3.6 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(1,3-thiazol-2-ylmethyl)sulfanyl]ethanone
1
(12): Yellow crystalline solid (170 mg, 55%): mp: 55–588C; H NMR
(270 MHz, CDCl3): d=1.60–1.90 (m, 12H), 2.03 (s, 3H), 3.32 (s, 2H),
3.90 (s, 2H), 7.22 (s, 1H), 8.77 ppm (s, 1H); LC/MS (APCI): m/z 308
[M+H]+; HRMS-FAB: m/z [M+Na]+ calcd for C16H21NNaOS2:
330.0962, found: 330.0965; HPLC: tR =2.6 min (98%) in 10% H2O/
CH3CN.
1-(Adamantan-1-yl)-2-{[(4-methyl-1,3-thiazol-2-yl)methyl]sulfany-
l}ethanone (13): Yellow oil (178 mg, 55%): 1H NMR (270 MHz,
CDCl3): d=1.55–1.88 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.03 (br s,
3H), 2.40 (s, 3H), 3.52 (s, 2H), 3.99 (s, 2H), 6.80 ppm (s, 1H); LC/MS
(APCI): m/z 322 [M+H]+; HRMS-FAB: m/z [M+Na]+ calcd for
C17H23NNaOS2: 344.1119, found: 344.1120; HPLC: tR =3.7 min (97%)
in 10% H2O/CH3CN.
5-(((2-(Adamantan-1-yl)-2-oxoethyl)thio)methyl)furan-2-carboxyl-
ic acid (19): A solution of 18 (860 mg, 2.47 mmol) in MeOH/H2O
(10–3 mL) was treated with KOH (345 mg) at RT and stirred for
12 h. Compound 19 was isolated by neutralisation with 2n HCl
and filtration as a white solid (620 mg, 75%): mp: 126–1278C;
1H NMR (270 MHz, CDCl3): d=1.62–1.80 (m, 6H), 1.83 (d, J=2.7 Hz,
6H), 2.03 (br s, 3H), 3.38 (s, 2H), 3.78 (s, 2H), 6.39 (d, J=3.3 Hz,
1H), 7.23 ppm (d, J=3.3 Hz, 1H); LC/MS (ESI): m/z 357 [M+Na]+;
HRMS-ESI: m/z [M+Na]+ calcd for C18H22NaO4S: 357.1136, found:
357.1122; HPLC: tR =1.80 min (97%) in 10% H2O/CH3CN.
Method C: Synthesis of the adamantyl ethanone sulfoxide and
sulfone derivatives 14–17: A cold solution of the corresponding
sulfanyl derivative (1 equiv) in CH2Cl2 (10 mL) was treated with m-
CPBA (2 equiv), and the mixture was stirred at ꢀ108C to 08C for
40 min. The mixture was then partitioned between CH2Cl2 and 5%
aq Na2CO3, and the organic phase was washed with brine, dried
over MgSO4, filtered and concentrated in vacuo to give the crude
product. The sulfoxide and sulfone were separated using flash
chromatography (EtOAc/CH2Cl2; gradient elution).
5-({[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}methyl)-N,N-dime-
thylfuran-2-carboxamide (20):
A
solution of 19 (293 mg,
0.88 mmol) in CH2Cl2 (10 mL) was treated with EDCI (184 mg,
0.96 mmol), HOBt (65 mg, 0.48 mmol) and DMAP (20 mg), followed
by Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at RT for
10 min and then treated with N,N-dimethylamine (DMA)/tetrahy-
drofuran (THF) (2m, 1 mL, 2.0 mmol). After stirring at RT for 16 h,
the mixture was partitioned between CH2Cl2 and 2% HCl solution.
The organic phase was washed with 5% aq NaHCO3 and brine,
dried over MgSO4, filtered and concentrated in vacuo. Purification
by flash column (CH2Cl2/EtOAc; gradient elution) yielded 20 as col-
1-(Adamantan-1-yl)-2-(thiophen-2-ylmethanesulfinyl)ethanone
(14):
A
white solid (115 mg, 36%): mp: 95–988C; 1H NMR
(270 MHz, CDCl3): d=1.62–1.81 (m, 12H), 2.05 (br s, 3H), 3.57 (d,
J=16 Hz, 1H), 3.86 (d, J=16 Hz, 1H), 4.36 (AB, 2H), 7.02–7.07 (m,
2H), 7.33 ppm (dd, J=5.2, 1.5 Hz, 1H); LC/MS (APCI): m/z 321
[MꢀH]+; HRMS-FAB: m/z [M+Na]+ calcd for C17H22O2S2Na:
345.0959, found: 345.0938; HPLC: tR =2.66 min (>99%) in 20%
H2O/CH3CN. 1-(Adamantan-1-yl)-2-(thiophen-2-ylmethanesupho-
nyl)ethanone (16): A white solid (68 mg, 21%): mp: 96–988C;
1H NMR (270 MHz, CDCl3): d=1.63–1.72 (m, 6H), 1.78 (d, J=2.7 Hz,
6H), 2.07 (br s, 3H), 3.95 (s, 2H), 4.73 (s, 2H), 7.03 (dd, J=5.2,
3.4 Hz, 1H), 7.20 (dd, J=3.4, 1.3 Hz, 1H), 7.36 ppm (dd, J=5.2,
1.3 Hz, 1H); LC/MS (APCI): m/z 337 [M+ꢀH]; HRMS-FAB: m/z [M+
1
ourless oil (185 mg, 58%): H NMR (270 MHz, CDCl3): d=1.62–1.78
(m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.02 (s, 3H), 3.09 (br s, 3H), 3.24
(br s, 3H), 3.33 (s, 2H), 3.75 (s, 2H2), 6.28 (d, J=3.3 Hz, 1H),
6.91 ppm (d, J=3.3 Hz, 1H); LC/MS (ESI): m/z 384 [M+Na]+;
HRMS-ESI: m/z [M+H]+ calcd for C20H28NO3S: 362.1790, found:
362.1770; HPLC: tR =2.43 min (97%) in 10% H2O/CH3CN.
Methyl 5-({[2-(adamantan-1-yl)-2-oxoethane]sulfinyl}methyl)fur-
an-2-carboxylate (21): Prepared using method C. A white solid
ChemMedChem 2011, 6, 1439 – 1451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1447

B. V. L. Potter et al.
MED
(35 mg, 21%): mp: 119–1208C; 1H NMR (270 MHz, CDCl3): d=1.64–
1.78 (m, 6H), 1.80 (d, J=2.7 Hz, 6H), 2.06 (br s, 3H), 3.79 (d, J=
16 Hz, 1H), 3.86 (s, 3H), 3.95 (d, J=16 Hz, 1H), 4.19 (d, J=14 Hz,
1H), 4.30 (d, J=14 Hz, 1H), 6.57 (d, J=3.5 Hz, 1H), 7.18 ppm (d,
J=3.6 Hz, 1H); LC/MS (ESI): m/z 387 [M+Na]+; HRMS-ESI: m/z
[M+H]+ calcd for C19H25O5S: 365.1423, found: 365.1410; HPLC:
tR =1.92 min (>99%) in 10% H2O/CH3CN. Methyl 5-({[2-(adaman-
tan-1-yl)-2-oxoethane]sulfonyl}methyl)furan-2-carboxylate (22):
Prepared using method C. A white solid (101 mg, 60%): mp: 135–
1368C; 1H NMR (270 MHz, CDCl3): d=1.64–1.78 (m, 6H), 2.02 (d,
J=2.6 Hz, 6H), 2.07 (br s, 3H), 3.86 (s, 3H), 4.10 (s, 2H), 4.68 (s,
2H), 6.63 (d, J=3.5 Hz, 1H), 7.16 ppm (d, J=3.3 Hz, 1H); LC/MS
(ESI): m/z 403 [M+Na]+; HRMS-ESI: m/z [M+Na]+ calcd for
C19H25O6S: 381.1372, found: 381.1360 [M+H]+; HPLC: tR =2.01 min
(>99%) in 10% H2O/CH3CN.
z [M+H]+ calcd for C15H22N3OS: 292.1484, found: 292.1484; HPLC:
tR =2.0 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-
ethanone (29): Prepared using method B. A white solid (670 mg,
1
87%): mp: 102–1058C; H NMR (270 MHz, CDCl3): d=1.65–1.80 (m,
6H), 1.90 (d, J=2.8 Hz, 6H), 2.06 (br s, 3H), 2.69 (s, 3H), 4.48 ppm
(s, 2H); LC/MS (ESI): m/z 309 [M+H]+; HRMS-ESI: m/z [M+Na]+
calcd for C15H20N2OS2Na: 331.0915, found: 331.0873; HPLC: tR =
2.7 min (>99%) in 10% H2O/CH3CN.
5-({[2-(Adamantan-1-yl)-2-oxoethane]sulfinyl}methyl)-N,N-dime-
thylfuran-2-carboxamide (30): Prepared using method C. A yellow
solid (160 mg, 52%): mp: 114–1168C; 1H NMR (270 MHz, CDCl3):
d=1.56–1.75 (m, 12H), 2.03 (br s, 3H), 4.06 (d, J=15 Hz, 1H), 4.39
(d, J=15 Hz, 1H), 7.10 (dd, J=5.1, 3.6 Hz, 1H), 7.48 (dd, J=3.4,
1.2 Hz, 1H), 7.65 ppm (dd, J=5.0, 1.3 Hz, 1H); LC/MS (APCI): m/z
307 [MꢀH]+; HRMS-FAB: m/z [M+Na]+ calcd for C16H20O2S2Na:
331.0802, found: 331.0780; HPLC: tR =2.7 min (>99%) in 10%
H2O/CH3CN. 5-({[2-(Adamantan-1-yl)-2-oxoethane]sulfonyl}meth-
yl)-N,N-dimethylfuran-2-carboxamide (34): Prepared using meth-
od C. A white solid (90 mg, 28%): mp: 117.5–1198C; 1H NMR
(270 MHz, CDCl3): d=1.61–1.74 (m, 6H), 1.75 (d, J=2.7 Hz, 6H),
2.04 (br s, 3H), 4.36 (s, 2H), 7.14 (dd, J=5.0, 3.7 Hz, 1H), 7.72–
7.76 ppm (m, 2H); LC/MS (APCI): m/z 323 [MꢀH]+; HRMS-FAB: m/z
[M+Na]+ calcd for C16H20O3S2Na: 347.0752, found: 347.0721;
HPLC: tR =2.25 min (98%) in 10% H2O/CH3CN.
5-({[2-(Adamantan-1-yl)-2-oxoethane]sulfonyl}methyl)furan-2-
carboxylic acid (23): Prepared using method C. A white solid
(97 mg, 46%): mp: 163–1658C; 1H NMR (270 MHz, CDCl3): d=
1.60–1.79 (m, 12H), 2.04 (br s, 3H), 4.15 (s, 2H), 4.69 (s, 2H), 6.58
(br s, 1H), 7.19 (br s, 1H); LC/MS (ESI): m/z 367 [M+H]+; HRMS-ESI:
m/z [M+H]+ calcd for C18H23O6S: 367.1215, found: 367.1209;
HPLC: tR =1.76 min (98%) in 10% H2O/CH3CN.
5-({[2-(Adamantan-1-yl)-2-oxoethane]sulfinyl}methyl)-N,N-dime-
thylfuran-2-carboxamide (24): Prepared using method C. A colour-
1
less oil (55 mg, 50%): H NMR (270 MHz, CDCl3): d=1.62–1.80 (m,
12H), 2.05 (br, 3H), 3.07 (br s, 3H), 3.23 (br s, 3H), 3.72 (d, J=
16 Hz, 1H), 3.97 (s, 3H), 3.95 (d, J=16 Hz, 1H), 4.19 (d, J=15 Hz,
1H), 4.31 (d, J=15 Hz, 1H), 6.59 (d, J=3.5 Hz, 1H), 6.96 ppm (d,
J=3.6 Hz, 1H); LC/MS (ESI): m/z 378 [M+H]+; HRMS-ESI: m/z [M+
H]+ calcd for C20H29NO4S: 378.1739, found: 378.1724; HPLC: tR =
1.73 min (>99%) in 10% H2O/CH3CN. 5-({[2-(Adamantan-1-yl)-2-
oxoethane]sulfonyl}methyl)-N,N-dimethylfuran-2-carboxamide
(25): Prepared using method C. A white solid (35 mg, 31%): mp:
1-(Adamantan-1-yl)-2-(1-methyl-1H-imidazole-2-sulfinyl)etha-
none (31): Prepared using method C. A yellow solid (170 mg,
56%): mp: 86–898C; 1H NMR (270 MHz, CDCl3): d=1.63–1.85 (m,
12H), 2.04 (br s, 3H), 3.93 (s, 3H), 4.51 (d, J=17 Hz, 1H), 4.91 (d,
J=17 Hz, 1H), 6.98 (d, J=1.0 Hz, 1H), 7.15 ppm (d, J=1.0 Hz, 1H);
LC/MS (APCI): m/z 307 [M+H]+; HRMS-FAB: m/z [M+H]+ calcd for
C16H23N2O2S: 307.1480, found: 307.1477; HPLC: tR =2.6 min (97%)
in 10% H2O/CH3CN. 1-(Adamantan-1-yl)-2-(1-methyl-1H-imida-
zole-2-sulfonyl)ethanone (35): Prepared using method C. A white
1
134–1358C; H NMR (270 MHz, CDCl3): d=1.62–1.77 (m, 6H), 1.79
1
(d, J=2.8 Hz, 6H), 2.07 (br s, 3H), 3.06 (s, 3H), 3.25 (s, 3H), 4.03 (s,
2H), 4.65 (s, 2H), 6.59 (d, J=3.3 Hz, 1H), 7.00 ppm (d, J=3.3 Hz,
1H); LC/MS (ESI): m/z 394 [M+H]+; HRMS-ESI: m/z [M+H]+ calcd
for C20H28NO5S: 394.1688, found: 394.1670; HPLC: tR =1.70 min
(98%) in 10% H2O/CH3CN.
solid (66 mg, 20%): mp: 124–1258C; H NMR (270 MHz, CDCl3): d=
1.61–1.74 (m, 12H), 2.04 (br s, 3H), 4.01 (s, 3H), 4.58 (s, 2H),
7.14 ppm (d, J=1.0 Hz, 1H); LC/MS (APCI): m/z 321 [MꢀH]+;
HRMS-FAB: m/z [M+H]+ calcd for C16H23N2O3S: 323.1429, found:
323.1418; HPLC: tR =2.0 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(4-methyl-4H-[1,2,4]triazole-3-sulfinyl)e-
thanone (32): Prepared using method C. A white solid (180 mg,
59%): mp: 124.5–1278C; 1H NMR (270 MHz, CDCl3): d=1.62–1.84
(m, 12H), 2.07 (br, 3H), 3.97 (s, 3H), 4.62 (d, J=15 Hz, 1H), 5.09 (d,
J=15 Hz, 1H), 8.20 ppm (s, 1H); LC/MS (ESI): m/z 306 [MꢀH]+;
HRMS-ESI: m/z [M+Na]+ calcd for C15H21N3O2SNa: 330.1252, found:
330.1223; HPLC: tR =2.1 min (97%) in 10% H2O/CH3CN. 1-(Ada-
mantan-1-yl)-2-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)ethanone
(36): Prepared using method C. A white solid (85 mg, 26%): mp:
1-(Adamantan-1-yl)-2-(thiophen-2-ylsulfanyl)-ethanone (26): Pre-
pared using method B. An Off-white solid (250 mg, 86%): mp: 69–
1
728C; H NMR (270 MHz, CDCl3): d=1.67–1.78 (m, 12H), 2.02 (br s
3H), 3.84 (s, 2H), 6.94 (dd, J=5.1, 3.2 Hz, 1H), 7.15 (dd, J=3.3,
1.5 Hz, 1H), 7.34 ppm (dd, J=5.2, 1.5 Hz, 1H); LC/MS (APCI): m/z
293 [M+H]+; HRMS-FAB: m/z [M+Na]+ calcd for C16H20OS2Na:
315.0853, found: 315.0838; HPLC: tR =3.6 min (>99%) in 10%
H2O/CH3CN.
1
1-(Adamantan-1-yl)-2-(1-methyl-1H-imidazol-2-ylsulfanyl)-etha-
none (27): Prepared using method B. An off-white solid (230 mg,
79%): mp: 65–698C; 1H NMR (270 MHz, CDCl3): d=1.63–1.81 (m,
6H), 1.82 (d, J=2.3 Hz, 6H), 2.03 (br s, 3H), 3.64 (s, 3H), 4,23 (s,
2H), 6.89 (d, J=1.2 Hz, 1H), 7.01 ppm (d, J=1.2 Hz, 1H); LC/MS
(APCI): m/z 291 [M+H]+; HRMS-FAB: m/z [M+H]+ calcd for
C16H23N2OS: 291.1531, found: 291.1524; HPLC: tR =3.0 min (>99%)
in 10% H2O/CH3CN.
149–1508C; H NMR (270 MHz, CDCl3): d=1.60–1.80 (m, 12H), 2.05
(br s, 3H), 4.02 (s, 3H), 4.71 (s, 2H), 8.17 ppm (s, 1H); LC/MS (ESI):
m/z 322 [MꢀH]+; HRMS-ESI: m/z [M+Na]+ calcd for
C15H21N3O3SNa: 346.1201, found: 346.1160; HPLC: tR =1.7 min
(97%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-(5-methyl-[1,3,4]thiadiazole-2-sulfinyl)e-
thanone (33): Prepared using method C. A white solid (180 mg,
1
56%): mp: 127–1298C; H NMR (270 MHz, CDCl3): d=1.66–1.79 (m,
1-(Adamantan-1-yl)-2-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-
ethanone (28): Prepared using method B. A white solid (340 mg,
58%): mp: 135–1368C; H NMR (270 MHz, CDCl3): d=1.60–1.80 (m,
6H), 1.87 (d, J=2.8 Hz, 6H), 2.05 (br s, 3H), 3.63 (s, 3H), 4.47 (s,
2H), 8.09 ppm (s, 1H); LC/MS (ESI): m/z 292 [M+H]+; HRMS-ESI: m/
6H), 1.82 (d, J=2.7 Hz, 6H), 2.06 (br s, 3H), 2.85 (s, 3H), 4.44 ppm
(q, J=15 Hz, 2H); LC/MS (ESI): m/z 325 [M+H]+; HRMS-ESI: m/z
[M+Na]+ calcd for C15H20N2O2S2Na: 347.0864, found: 347.0817;
HPLC: tR =2.0 min (99%) in 10% H2O/CH3CN. 1-(Adamantan-1-yl)-
2-(5-methyl-[1,3,4]thiadiazole-2-sulfonyl)ethanone (37): Prepared
1
1448
www.chemmedchem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2011, 6, 1439 – 1451

11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
using method C. A white solid (60 mg, 18%): mp: 111–1138C;
1H NMR (270 MHz, CDCl3): d=1.65–1.75 (m, 6H), 1.76 (d, J=2.7 Hz,
6H), 2.06 (br s, 3H), 2.89 (s, 3H), 4.75 ppm (s, 2H); LC/MS (ESI): m/z
341 [M+H]+; HRMS-ESI: m/z [M+Na]+ calcd for C15H20N2O3S2Na:
363.0813, found: 363.0769; HPLC: tR =2.0 min (97%) in 10% H2O/
CH3CN.
methyl ketone (643 mg, 2.5 mmol), and stirred at RT overnight. The
mixture was partitioned between CH2Cl2 and brine, and the organ-
ic phase was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash column (CH2Cl2/CH3OH;
gradient elution) yielded 41 as white solid (550 mg, 66%): mp:
1
109–1118C; H NMR (270 MHz, CDCl3): d=1.60–1.82 (m, 6H), 1.86
(d, J=2.8 Hz, 6H), 2.04 (br s, 3H), 3.34 (s, 3H), 3.59 (s, 3H), 4.44 (s,
2H), 4.58 ppm (s, 2H); LC/MS (ESI): m/z 336 [M+H]+; HRMS-ESI: m/
z [M+H]+ calcd for C17H26N3O2S: 336.1745, found: 336.1730; HPLC:
tR =1.8 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(4,5-dimethyl-1,2,4-triazol-3-yl)sulfanyl]e-
thanone (38): A mixture of 2-acetyl-N-methylhydrazinecarbothioa-
mide (441 mg, 3 mmol) in 2n aq NaOH (4 mL) was refluxed under
nitrogen for 4 h, cooled to RT and concentrated in vacuo. The resi-
due was redissolved in CH3CN (12 mL), treated with adamantan-1-
yl bromomethyl ketone (514 mg, 2 mmol) and stirred at RT over-
night. The reaction was partitioned between CH2Cl2 and water, and
the organic phase was washed with brine, dried over MgSO4, fil-
tered and concentrated in vacuo. Purification by flash column
(CH2Cl2/MeOH; gradient elution) yielded 38 as white solid (290 mg,
Methyl 2-(5-{[2-(adamantan-1-yl)-2-oxoethyl]sulfanyl}-4-methyl-
4H-1,2,4-triazol-3-yl)acetate (42): A solution of 4-methyl-3-thiose-
micarbazide (316 mg, 3.0 mmol) in CH2Cl2 (10 mL) was treated with
pyridine (1.2 mL), followed by 2-cyanoacetyl chloride (312 mg,
3 mmol) at 08C. The mixture was stirred at RT overnight, and then
concentrated in vacuo. The residue was redissolved in 2n aq
NaOH (6 mL) and refluxed under nitrogen for 6 h. The reaction was
cooled to RT, treated with adamantan-1-yl bromomethyl ketone
(643 mg, 2.5 mmol), and stirred at RT overnight. The mixture was
partitioned between CH2Cl2 and brine, and the organic phase was
washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. The crude residue was redissolved in MeOH (10 mL) and
treated with HCl (37%, 0.5 mL) and the mixture was refluxed for
6 h. Aqueous work-up gave a clear oil, and subsequent purification
by flash column (CH2Cl2/CH3OH; gradient elution) yielded 42 as
white solid (344 mg, 38%): mp: 135–1378C; 1H NMR (270 MHz,
CDCl3): d=1.59–1.81 (m, 6H), 1.87 (d, J=2.8 Hz, 6H), 2.02 (br s,
3H), 3.52 (s, 3H), 3.72 (s, 3H), 3.86 (s, 2H), 4.46 ppm (s, 2H); LC/MS
(ESI): m/z 364[M+H]+; HRMS-ESI: m/z [M+H]+ calcd for
C18H26N3O3S: 364.1695, found: 364.1698; HPLC: tR =1.1 min (99%)
in 10% H2O/CH3CN.
1
41%): mp: 113–1148C, H NMR (270 MHz, CDCl3): d=1.62–1.80 (m,
6H), 1.85 (d, J=2.8 Hz, 6H), 2.15 (br s, 3H), 2.39 (s, 3H), 3.49 (s,
3H), 4.39 ppm (s, 2H); LC/MS (ESI): m/z 306 [M+H]+; HRMS-ESI: m/
z [M+H]+ calcd for C16H24N3OS: 306.1640, found: 306.1627; HPLC:
tR =1.8 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[5-methyl-4-(propan-2-yl)-4H-1,2,4-triazol-
3-yl]sulfanyl}ethanone (39): A mixture of 2-acetyl-N-isopropylhy-
drazinecarbothioamide (780 mg, 4.46 mmol) in 2n aq NaOH (5 mL)
was refluxed under nitrogen for 6 h, cooled to RT and concentrated
in vacuo. The residue was redissolved in CH3CN (15 mL), treated
with adamantan-1-yl bromomethyl ketone (900 mg, 3.5 mmol) and
stirred at RT overnight. The reaction was partitioned between
CH2Cl2 and water, and the organic phase was washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. Purification
by flash column (CH2Cl2/EtOAc; gradient elution) yielded 39 as
white solid (510 mg, 44%): mp: 119–1218C, 1H NMR (270 MHz,
CDCl3): d=1.49 (d, J=6.8 Hz, 6H), 1.65–1.85 (m, 6H), 1.87 (d, J=
2.5 Hz, 6H), 2.03 (br s, 3H), 2.45 (s, 3H), 4.45 ppm (m, 3H); LC/MS
(ESI): m/z 334 [M+H]+; HRMS-ESI: m/z [M+H]+ calcd for
C18H28N3OS: 334.1953, found: 334.1953; HPLC: tR =2.1 min (99%) in
10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(4,5-dicyclopropyl-4H-1,2,4-triazol-3-yl)-
sulfanyl]ethanone (43): Prepared using method B. A white solid
1
(295 mg, 65%): mp: 117–1198C; H NMR (270 MHz, CDCl3): d=1.02
(m, 8H), 1.59–1.83 (m, 7H), 1.82 (d, J=2.8 Hz, 6H), 2.01 (br s, 3H),
3.15 (m, 1H), 4.39 ppm (s, 2H); LC/MS (ESI): m/z 358 [M+H]+;
HRMS-ESI: m/z [M+H]+ calcd for C20H28N3OS: 358.1953, found:
358.1943; HPLC: tR =1.7 min (98%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-[(5-cyclopropyl-4-methyl-4H-1,2,4-triazol-
3-yl)sulfanyl]ethanone (40): A mixture of 2-(cyclopropanecarbon-
yl)-N-methylhydrazinecarbothioamide (700 mg, 4.05 mmol) in 2n
aq NaOH (5 mL) was refluxed under nitrogen for 5 h, cooled to RT
and concentrated in vacuo. The residue was redissolved in CH3CN
(5 mL), treated with adamantan-1-yl bromomethyl ketone (771 mg,
3.0 mmol) and stirred at RT overnight. The reaction was partitioned
between CH2Cl2 and water, and the organic phase was washed
with brine, dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash column (CH2Cl2/EtOAc; gradient elution) yield-
ed 40 as white solid (390 mg, 39%): mp: 96–97.58C, 1H NMR
(270 MHz, CDCl3): d=1.00 (m, 4H), 1.60–1.80 (m, 7H), 1.83 (d, J=
2.8 Hz, 6H), 2.01 (br s, 3H), 3.57 (s, 3H), 4.35 ppm (s, 2H); LC/MS
(ESI): m/z 332 [M+H]+; HRMS-ESI: m/z [M+H]+ calcd for
C18H26N3OS: 332.1796, found: 332.1796; HPLC: tR =1.9 min (99%) in
10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-tria-
zol-3-yl]sulfanyl}ethanone (44): Prepared using method B. A white
solid (395 mg, 53%): mp: 156–1578C; 1H NMR (270 MHz, CDCl3):
d=1.66–1.82 (m, 6H), 1.88 (d, J=2.8 Hz, 6H), 2.05 (br s, 3H), 3.73
(s, 3H), 4.46 (s, 2H), 7.14 (t, J=4.9 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H),
7.47 ppm (d, J=4.9 Hz,1H); LC/MS (ESI): m/z 374 [M+H]+; HRMS-
ESI: m/z [M+H]+ calcd for C19H24N3OS2: 374.1361, found: 374.1362;
HPLC: tR =2.1 min (>99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[5-(dimethylamino)-1,3,4-thiadiazol-2-yl]-
sulfanyl}ethanone (45): A solution of N,N-dimethylhydrazinecarbo-
thioamide (477 mg, 4 mmol) in DMF (6 mL) was treated with Et3N
(1 mL), followed by CS2 (0.4 mL). The mixture was stirred at RT
overnight and then at 608C for 5 h. The reaction was cooled to RT,
treated with adamantan-1-yl bromomethyl ketone (514 mg,
2.0 mmol) and stirred at RT overnight. The mixture was partitioned
between EtOAc and brine, and the organic phase was washed with
brine, dried over MgSO4, filtered and concentrated in vacuo. Purifi-
cation by flash column (CH2Cl2/EtOAc; gradient elution) yielded 45
as an off-white solid (365 mg, 54%): mp: 150–1518C; 1H NMR
(270 MHz, CDCl3): d=1.65–1.82 (m, 6H), 1.85 (d, J=2.8 Hz, 6H),
2.03 (br s, 3H), 3.11 (s, 6H), 4.40 ppm (s, 2H); LC/MS (ESI): m/z 338
[M+H]+; HRMS-ESI: m/z [M+H]+ calcd for C16H24N3OS2: 338.1361,
found: 338.1353; HPLC: tR =2.4 min (99%) in 10% H2O/CH3CN.
1-(Adamantan-1-yl)-2-{[5-(methoxymethyl)-4-methyl-4H-1,2,4-tri-
azol-3-yl]sulfanyl}ethanone (41): A solution of 4-methyl-3-thiose-
micarbazide (526 mg, 5.0 mmol) in CH2Cl2 (10 mL) was treated with
pyridine (1.2 mL), followed by metholoxyacetyl chloride (0.46 mL,
5 mmol) at 08C. The mixture was stirred at RT overnight, then con-
centrated in vacuo. The residue was redissolved in 2n aq NaOH
(6 mL), and the solution was refluxed under nitrogen for 6 h. The
reaction was cooled to RT, treated with adamantan-1-yl bromo-
ChemMedChem 2011, 6, 1439 – 1451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1449

B. V. L. Potter et al.
MED
1-(Adamantan-1-yl)-2-{[5-(methylsulfanyl)-1,3,4-thiadiazol-2-yl]-
sulfanyl}ethanone (46): Prepared using method B. A white solid
(310 mg, 91%): mp: 133.5–1358C; 1H NMR (270 MHz, CDCl3): d=
1.65–1.83 (m, 6H), 1.89 (d, J=2.7 Hz, 6H), 2.06 (br s, 3H), 2.72 (s,
3H), 4.47 ppm (s, 2H); LC/MS (ESI): m/z 341 [M+H]+; HRMS-ESI: m/
z [M+H]+ calcd for C15H21N2OS3: 341.0816, found: 341.0807; HPLC:
tR =3.1 min (98%) in 10% H2O/CH3CN.
363.0813, found: 363.0795; HPLC: tR =1.9 min (98%) in 10% H2O/
CH3CN.
Acknowledgements
This work was supported by Sterix Ltd,a member of the Ipsen
Group, and by the Wellcome Trust Programme Grant 082837 to
B.V.L.P. We thank Alison C. Smith for technical assistance, Nicole
Muller and Isabelle Viossat for CYP inhibition and metabolic sta-
bility studies. We also thank the EPSRC national mass spectrome-
try service centre at the University of Wales Swansea for taking
some high resolution accurate mass measurements.
1-(Adamantan-1-yl)-2-{[5-(ethylsulfanyl)-1,3,4-thiadiazol-2-yl]sul-
fanyl}ethanone (47): Prepared using method B. A colourless oil
(277 mg, 71%): 1H NMR (270 MHz, CDCl3): d=1.30 (t, J=7.2 Hz,
3H,),1.63–1.81 (m, 6H), 1.88 (d, J=2.7 Hz, 6H), 2.03 (br s, 3H), 2.73
(q, J=7.2 Hz, 2H), 4.47 ppm (s, 2H); LC/MS (ESI): m/z 355 [M+H]+;
HRMS-ESI: m/z [M+H]+ calcd for C16H23N2OS3: 355.0973, found:
355.0968; HPLC: tR =2.7 min (98%) in 10% H2O/CH3CN.
Keywords: 11b-HSD1 inhibitors
·
adamantyl ethanones
·
1-(Adamantan-1-yl)-2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]e-
diabetes
·
hydroxysteroid dehydrogenases
·
metabolic
thanone (48): Prepared using method B. A white solid (504 mg,
91%): mp: 198–1998C; H NMR (270 MHz, CDCl3): d=1.62–1.80 (m,
1
syndrome
6H), 1.85 (d, J=2.8 Hz, 6H), 2.15 (br s, 3H), 2.39 (s, 3H), 3.49 (s,
3H), 4.39 ppm (s, 2H); LC/MS (ESI): m/z 310 [M+H]+; HRMS-ESI: m/
z [M+H]+ calcd for C14H20N3OS2: 310.1048, found: 310.1037; HPLC:
tR =2.0 min (99%) in 10% H2O/CH3CN.
[1] U. C. T. Oppermann, B. Persson, H. Jçrnvall, Eur. J. Biochem. 1997, 249,
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none (49): Prepared using method C. A white solid (165 mg, 75%):
mp: 202–2048C; H NMR (270 MHz, CDCl3): d=1.62–1.80 (m, 6H),
1.85 (d, J=2.8 Hz, 6H), 2.15 (br s, 3H), 2.39 (s, 3H), 3.49 (s, 3H),
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1
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AcOH (2 mL) was added Ac2O (0.1 mL). The mixture was stirred at
RT overnight, then diluted with water (3 mL). The precipitate was
collected, washed with water and dried in vacuo to give 50 as a
white solid (228 mg, 89%): mp: 208–2108C; 1H NMR (270 MHz,
CDCl3); d=1.66–1.82 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.12 (br s,
3H), 2.41 (s, 3H), 4.38 ppm (s, 2H); LC/MS (ESI): m/z 352 [M+H]+;
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(89 mg, 50%): mp: 198–2018C; 1H NMR (270 MHz, CDCl3): d=
1.65–1.85 (m, 12H), 2.06 (br s, 3H), 2.45 (s, 3H), 4.36 (d, J=16 Hz,
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1
11%): mp: 216–2188C; H NMR (270 MHz, CDCl3): d=1.62–1.80 (m,
12H), 2.07 (br s, 3H), 2.47 (s, 3H), 4.67 ppm (s, 2H); LC/MS (ESI): m/
z 384 [M+H]+; HRMS-ESI: m/z [M+H]+ calcd for C16H22N3O4S2:
384.1051, found: 384.1087; HPLC: tR =1.7 min (99%) in 10% H2O/
CH3CN.
Sodium 1-(adamantan-1-yl)-2-(5-methyl-1,3,4-thiadiazole-2-sul-
fonyl)ethen-1-ol (53): A solution of 37 (68 mg, 0.2 mmol) in 2% aq
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3H), 2.68 (s, 3H), 4.61 ppm (s, 1H); LC/MS (ESI): m/z 341 [parent
M+H]+; HRMS-ESI: m/z [parent M+Na]+ calcd for C15H20N2O3S2Na:
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Received: March 17, 2011
Published online on May 23, 2011
ChemMedChem 2011, 6, 1439 – 1451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1451