Discovery of adamantyl ethanone derivatives as potent 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors

MED

DOI: 10.1002/cmdc.201000081

Discovery of Adamantyl Ethanone Derivatives as Potent

11b-Hydroxysteroid Dehydrogenase Type 1 (11b-HSD1)

Inhibitors

Xiangdong Su,^[a]Fabienne Pradaux-Caggiano,^[a]Mark P. Thomas,^[a]Michelle W. Y. Szeto,^[a]

Heather A. Halem,^[b]Michael D. Culler,^[b]Nigel Vicker,^[a]and Barry V. L. Potter*^[a]

11b-Hydroxysteroid dehydrogenases (11b-HSDs) are key en-

zymes regulating the pre-receptor metabolism of glucocorti-

coid hormones. The modulation of 11b-HSD type 1 activity

with selective inhibitors has beneficial effects on various condi-

tions including insulin resistance, dyslipidemia and obesity. In-

hibition of tissue-specific glucocorticoid action by regulating

11b-HSD1 constitutes a promising treatment for metabolic and

cardiovascular diseases. A series of novel adamantyl ethanone

compounds was identified as potent inhibitors of human 11b-

HSD1. The most active compounds identified (52, 62, 72, 92,

103 and 104) display potent inhibition of 11b-HSD1 with IC₅₀

values in the 50–70 nm range. Compound 72 also proved to

be metabolically stable when incubated with human liver mi-

crosomes. Furthermore, compound 72 showed very weak in-

hibitory activity for human cytochrome P450 enzymes and is

therefore a candidate for in vivo studies. Comparison of the

publicly available X-ray crystal structures of human 11b-HSD1

led to docking studies of the potent compounds, revealing

how these molecules may interact with the enzyme and cofac-

tor.

Introduction

Metabolic syndrome is a condition characterised by a cluster of

disorders including insulin resistance, glucose intolerance, vis-

ceral obesity, hypertension and dyslipidemia, which are widely

recognised as high risk factors for cardiovascular disease.^[1]The

rapidly increasing prevalence of metabolic syndrome has fo-

cused the need for novel treatments, thus attracting intense

interest from pharmaceutical research laboratories across aca-

demia and industry. Glucocorticoid hormones play essential

roles in the regulation of carbohydrate, lipid and bone metab-

olism, modulation of inflammatory responses, brain function

and stress. Excessive glucocorticoid action is, in many aspects,

associated with insulin and leptin resistance, leading to the de-

velopment of obesity, type 2 diabetes and other metabolic and

cardiovascular disorders, the major underlying causes of meta-

bolic syndrome.^[2–5]Numerous studies have implicated gluco-

corticoid action in the regulation of hepatic gluconeogenesis

and lipogenesis, glucose uptake and lipid oxidation in skeletal

muscle, and the production of angiotensinogen.^[6–8]Patients

with Cushing’s syndrome have increased glucocorticoid expo-

sure and exhibit similar symptoms compared with those with

metabolic syndrome, including insulin resistance, high adiposi-

ty, dyslipidemia and hypertension.^[9]These metabolic abnormi-

ties in Cushing’s syndrome could be improved to a certain

degree by decreasing the excessive glucocorticoid action

through surgery or glucocorticoid receptor antagonist treat-

ment.^[10–12]The link between the similar phenotype of Cush-

ing’s syndrome and metabolic syndrome suggested the poten-

tial treatments of individual indications of metabolic syndrome

by suppression of glucocorticoid activity.^[13]

type 2 diabetes.^[14]Therefore, it is speculated that intercellular

levels of glucocorticoid, regulated by pre-receptor metabolism,

are responsible for metabolic abnormalities. The pre-receptor

metabolism of the active glucocorticoid cortisol (2a) and its

precursor cortisone (1a) is mediated by 11b-hydroxysteroid de-

hydrogenase isozymes (11b-HSDs), which are microsomal en-

zymes from the short-chain dehydrogenase/reductase (SDR)

superfamily.^[15]Currently, two different 11b-HSD isozymes (11b-

HSD1 and 11b-HSD2) have been reported in humans. The 11b-

HSD1 isoform, highly expressed in liver and adipose tissue,

converts cortisone (1a) in humans (11-dehydrocorticosterone

1b in rodents) to the active glucocorticoid cortisol (2a) (corti-

costerone 2b in rodents) in a NADPH dependent manner,

thereby locally amplifying the glucocorticoid action in specific

tissues (Scheme 1).^[16,17]The 11b-HSD2 isoform is exclusively

NAD⁺dependent and is mainly found in mineralocorticoid

target tissues, such as the kidney and colon. The function of

11b-HSD2 is in inactivating physiological glucocorticoid cortisol

to inactive cortisone in specific tissues, thereby preventing glu-

cocorticoid occupation of the mineralocorticoid receptor (MR),

which may lead to sodium retention, hypokalemia and hyper-

tension.^[18,19]

[a] Dr. X. Su, Dr. F. Pradaux-Caggiano, Dr. M. P. Thomas, Dr. M. W. Y. Szeto,

Dr. N. Vicker, Prof. B. V. L. Potter

Medicinal Chemistry, Department of Pharmacy and Pharmacology and

Sterix Ltd., University of Bath, Bath, BA27AY (UK)

Fax: (+44)1225-386114

E-mail: B.V.L.Potter@bath.ac.uk

However, circulating glucocorticoid levels are not elevated in

patients with the common form of obesity or overweight

[b] Dr. H. A. Halem, Dr. M. D. Culler

IPSEN, Biomeasure Inc., 27 Maple Street, Milford, MA 01757 (USA)

1026

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

amples of potent 11b-HSD1 inhibitors on which advanced pre-

clinical studies or clinical studies have been performed.^[28,41–46]

To discover novel, clinically useful inhibitors of 11b-HSD1, it

is important to have an array of structural types of inhibitors,

as the physicochemical properties of the compounds will de-

termine tissue distribution, hypothalamic–pituitary–adrenal

axis effects, and, ultimately, clinical utility. Therefore, we per-

formed optimisation on hit compounds 8 and 9, which we dis-

covered previously, to improve potency.^[47,48]We synthesised

compounds containing an adamantyl group linked to an aro-

matic unit through a multi-atom linker with a carbonyl group

attached to the adamantane as illustrated by general structure

10. These target compounds were screened for their inhibitory

Scheme 1. Interconversion of glucocorticoid hormones catalysed by 11b-

HSDs.

Studies revealed that 11b-HSD1 expression is increased in

the adipose tissue of obese subjects suggesting the possibility

of tissue-specific glucocorticoid excess.^[20,21]Transgenic mice

overexpressing 11b-HSD1 selectively in adipose tissue exhibit-

ed insulin-resistant diabetes, hyperlipidemia and visceral obesi-

ty.^[22]Conversely, overexpression of 11b-HSD2 in transgenic

mice resulted in greater insulin sensitivity, glucose tolerance

and resistance to body weight gain on a high-fat diet.^[23]In ad-

dition, the 11b-HSD1 knock-out mice are resistant to stress-in-

duced hyperglycaemia and have decreased cholesterol and tri-

glyceride levels.^[24,25]It has also been shown that the modula-

tion of 11b-HSD1 activity with selective inhibitors has beneficial

effects on various conditions, including insulin resistance, dysli-

pidemia and obesity.^[26–28]Furthermore, clinical studies showed

that treatment with carbenoxolone, a nonselective inhibitor of

11b-HSDs, results in increased hepatic insulin sensitivity along

with decreased glucose production.^[29,30]More recently, positive

proof-of-concept results from a 28 day phase IIa clinical trial

with the 11b-HSD1 inhibitor INCB013739 (structure unknown)

were reported by Incyte. In this trial, the treatment of type 2

diabetes mellitus patients with INCB013739 for 28 days signifi-

cantly improved hepatic and peripheral insulin sensitivity and

decreased fasting plasma glucose, low density lipoprotein and

total cholesterol levels.^[31]Inhibition of tissue-specific glucocor-

ticoid action by regulating 11b-HSD1 constitutes a promising

treatment for metabolic and cardiovascular diseases and there-

fore has attracted considerable attention over the last few

years.^[13,32–35]Increased research efforts by the pharmaceutical

industry have led to the discovery of numerous types of

potent, selective 11b-HSD1 inhibitors, and the progress in this

area has been recently reviewed.^[35–40]Compounds 3–7 are ex-

activity against human 11b-HSD1 in a HEK293 cell-based assay.

Herein, we report the discovery and the structure–activity rela-

tionships of some adamantyl ethanone compounds as potent

inhibitors of 11b-HSD1.

Results and Discussion

Chemistry

The target compounds 11–14 listed in Table 1, containing an

amino ethanone linker, were synthesised by a nucleophilic cou-

pling reaction between the aromatic amine and an aryl bromo-

methyl ketone or 1-adamantyl bromomethyl ketone in the

presence of a base (Scheme 2).

Scheme 2. Synthesis of the ethanone amine linker compounds 11–14. Re-

agents and conditions: a) ArNH₂, K₂CO₃, CH₃CN or EtOH, RT, 12–24 h, 40–

70%.

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1027

B. V. L. Potter et al.

MED

Similarly, target compounds 15–39, with an ethanone ether

linker, were generated by a nucleophilic coupling reaction be-

tween the corresponding phenols or benzyl alcohols and 1-

adamantyl bromomethyl ketone under basic conditions in

moderate to quantitative yields (Scheme 3).

ide 83–90 and sulfone analogues 91–99 by oxidation with m-

CPBA at low temperature. Normally, the oxidation would pro-

duce both the sulfoxide (major) and the sulfone (minor); in

some cases when only the sulfoxide was obtained, further oxi-

dation with m-CPBA at room temperature was used to prepare

the sulfone. Compounds 101–104 with a carboxamide sub-

stituent on the meta position of the phenyl ring were synthes-

ised from 100 by an amide coupling to give 101 or 102 fol-

lowed by oxidation of 102 to yield 103 and 104 (Scheme 5).

Scheme 3. Synthesis of ethanone ether linker compounds 15–39 (3* and 4*

indicate points of attachment to the phenyl ring). Reagents and conditions:

a) ArOH, K₂CO₃, acetone or DMF, RT, 8–24 h, 37–100%; b) ArCH₂OH, NaH,

THF, 08C; c) ArCH₂OH, tBuOK, toluene, RT, 16–36 h, 15–43%.

Target compounds 42–58, with a carboxamide substituent

on the phenyl ring, were synthesised in three steps by a nucle-

ophilic substitution reaction of 1-adamantyl bromomethyl

ketone with the corresponding methyl-ester-substituted phe-

nols to form compounds 23 or 24, then saponification of the

esters to give 40 or 41, followed by amide coupling of the re-

quired amine and phenyl acid (Scheme 4). Similarly, com-

pounds 61–73, with an acetamide substituent on the phenyl

ring, were also prepared by the same method from 59 or 60

(obtained from the hydrolysis of 25 or 32, respectively) as illus-

trated in Scheme 4.

Scheme 5. Synthesis of ethanone sulfur linker compounds 74–104. Reagents

and conditions: a) m-CPBA, CH₂Cl₂, ꢀ10!08C, 20–90 min, 20–80%; b) m-

CPBA, CH₂Cl₂, RT, 4–8 h, 29–94%; c) NHR¹R², EDCI, DMAP, Et₃N, CH₂Cl₂, RT,

16 h, 65–68%.

Structure–activity relationships

The coupling reaction of 1-adamantyl bromomethyl ketone

with the corresponding mercaptans in the presence of triethyl-

amine in acetonitrile generated the target compounds 74–82,

which were then transformed into their corresponding sulfox-

The target compounds were examined for their inhibitory ac-

tivity against 11b-HSD1 on HEK293 cell line. Because nontrans-

fected HEK293 cells lack endogenous 11b-HSD1 activity, this

cell line has been shown to be a suitable system for evaluating

11b-HSD1 activity after being transfected with the

plasmid for expression of 11b-HSD1. The percent in-

hibition of 11b-HSD1 was measured at 1 mm in dupli-

cate. The IC₅₀values are reported as the mean value

of three measurements with variance of less than

20%.

Our earlier work identified a class of phenyl car-

boxamides and phenyl sulfonamides as inhibitors of

human 11b-HSD1.^[47,48]Compounds 8 and 9 exhibited

moderate activity against purified human 11b-HSD1

with both having IC₅₀values of 3.2 mm, but had only

very weak inhibition in the cell-based assay (<50%

inhibition at 10 mm).^[47,48]The carboxamide group of

Scheme 4. Synthesis of ethanone ether linker compounds 40–73. Reagents and condi-

tions: a) NHR¹R², EDCI, DMAP, Et₃N, CH₂Cl₂, RT, 16–24 h, 25–88%.

compound 8 was then modified to break the conju-

1028

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

gation in the linker. Compounds with an extended ethanone

tethered to the methylbenzothiazole unit through an amino

group were synthesised and screened for inhibition of 11b-

HSD1. Compounds 11 and 12 showed improved activity on a

transfected HEK293 cell line with IC₅₀values of 6.4 and 5.8 mm,

respectively (Table 1).

Table 2. In vitro inhibitory activity of acetamido benzene derivatives.

Compd

X

Acetamide

R

IC₅₀[nm]

16

17

18

19

20

21

22

74

75

83

84

91

92

O

S

SO

SO₂

p

m

p

m

p

m

p

–

211

285

68%^[a]

49%^[a]

61%^[a]

894

897

2037

313

105

151

167

58

3-Me

3-Cl

2-Cl

3-F

2-Me

–

Table 1. In vitro inhibition of compounds 11–15.

Compd

X

R

Ar^[a]

IC₅₀[nm]

11

NH

4-Cl-Ph

6400

m

p

12

NH

2,4-di-Cl-Ph

5800

–

[a] Percent inhibition measured at a concentration of 1 mm.

13

14

15

NH

O

1-Adamantyl

302

90

4-Acetamidophenyl

positions. Further modifications were performed by introduc-

ing a halogen or methyl substituent in the 2- or 3-positions on

the 4-acetaminophenyl unit to give compounds 18–22. With

3-fluoro or 2-methyl substituents, moderate inhibition of 11b-

HSD1 was observed for compounds 21 and 22, with IC₅₀

values of ~900 nm, giving about a fourfold decrease in activity

compared with 16. These substitutions might be affecting the

spatial position of the aryl ring or the acetamide group result-

ing in some loss of activity. Compounds 18–20 with methyl or

chloro substituents showed only moderate inhibition when

tested at 1 mm. The changes in the substituent in compounds

18–22 are not dramatic and so the loss of activity with these

compounds compared with 16 indicates a lack of tolerance to

substitution in this region. Surprisingly, when the ethanone

ether linker was altered to a similar ethanone sulfide linker, the

meta-acetamido compound (74) showed about a sevenfold

loss of activity with an IC₅₀value of only ~2 mm. Nevertheless,

the oxidation of the sulfide to the sulfoxide or sulfone raised

the inhibitory activity into the 100 nm range (83 and 91), sug-

gesting the oxygen or the sulfur atom possibly forms further

interactions with the enzyme or alters the geometry of the

molecule placing the adamantyl and/or the acetamidophenyl

group in a position with improved binding in the active site.

The same principle was applied to the para-acetamido series

with similar encouraging results. Compounds 75, 84 and 92

exhibited good activity with IC₅₀values of 313 nm, 151 nm and

58 nm, respectively. The activity of compound 75 is 6.5-fold

more potent than 74, a dramatic leap in activity for such a

small change, probably indicating a subtle electronic effect in

this region. The results for compounds 84 and 92 suggest that

the ethanone sulfone or sulfoxide moieties can not only alter

the geometry of the compound but are likely to enable addi-

tional hydrogen-bond interactions with the enzyme. The SO₂

group is found as part of linker system in known potent inhibi-

tors.^[41,42]Compound 92 with an IC₅₀value of 58 nm is the

most active in this series and is indeed a potent novel inhibitor

of human cellular 11b-HSD1.

4755

*

[a] : Indicates point of attachment.

The adamantyl moiety has appeared in several potent 11b-

HSD1 inhibitors.^[28,43]The replacement of the chlorinated

phenyl group with a more hydrophobic adamantyl moiety was

a successful attempt to produce more potent compounds. The

activity of compound 13 increased by ~20-fold with an IC₅₀

value of 302 nm, which indicated that the adamantyl group

was highly favoured with such a linker system possibly due to

the hydrophobic interactions in the binding region. However,

changing the amino group in the linker to oxygen was not

well tolerated, and this modification lowered the inhibition to

the same level as compound 15 with an IC₅₀value of 4.8 mm.

The reason for this loss of activity could be a geometrical

change in the linker affecting the position of the biaryl unit or

the ability of the amino group in the linker to act as a hydro-

gen-bond donor giving added interactions with the protein

backbone. The introduction of a 4-acetamidophenyl group, a

more flexible aromatic motif than the benzothiazole group,

gave compound 14 with ~3.5-fold improvement in activity

and an IC₅₀value of 90 nm. The 4-acetamido moiety on the

phenyl ring has both hydrogen-bond accepting and donating

capabilities and may participate in a hydrogen bonding net-

work with amino acid residues in the active site.

A series of compounds with phenyl rings substituted with

hydrogen bonding groups, such as an acetamide, was then

synthesised (Table 2). The ethanone amino linker was replaced

with an ethanone ether linker to give compounds 16 and 17; a

loss of two- to threefold activity relative to 14 was observed,

but the activity was retained with IC₅₀values of ~200–300 nm.

These results suggest that an oxygen linker can indeed be tol-

erated in the case of a monocyclic aromatic ring, and that the

acetamido substituent is acceptable at either the para or meta

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1029

B. V. L. Potter et al.

MED

Based on the positive results from the acetamido series, the

possibility of altering the acetamido phenyl unit to a benza-

mide or phenylacetamide group was explored, as both of

these moieties have hydrogen bonding capacity in the aromat-

ic region. This would allow diverse substitution on the phenyl

ring. Four structurally different subfamilies of compounds were

made from readily available intermediates: para- or meta-ben-

zamides with an ethanone linker (Tables 3 and 4), para-phenyl-

283 nm, suggesting possibly a further aromatic interaction in

that area. However, if another degree of rotation was given to

the aromatic ring, as in the case of a benzyl-substituted com-

pound (49), the activity decreased by sevenfold. A similar

result was observed with a 2-furfuryl substituent (50).

Moving the carboxamide group from the para to the meta

position led to some interesting findings. The nonsubstituted

meta-benzamide 51 exhibited only moderate inhibitory activity

with an IC₅₀value of 1 mm, a ninefold decrease relative to the

para analogue 42, whereas the 3-methylbenzamide 52 showed

very good potency with an IC₅₀value of 68 nm. It is possible

that the methyl group in the meta position is able to form hy-

drophobic interactions in the restricted space of the enzyme

pocket, whereas a methyl group in the para position is not

placed to pick up these additional interactions. The tendency

to lose activity was observed for bulkier groups similar to the

para-substituted series in Table 3, as moving from ethyl (53), to

isopropyl (54) or tert-butyl (55) showed a decrease of activity.

The 2-furfuryl analogue 56 was better tolerated than the

benzyl 57 and phenyl 58 derivatives, with an IC₅₀value of

229 nm versus 527 and 876 nm, respectively. This observation

is different to the para-carboxamide series suggesting that the

aromatic interaction with the enzyme is restricted in certain

areas. When the oxygen atom of the linker was substituted for

a sulfur atom, the N-methyl- and N,N-dimethylbenzamide com-

pounds 101 and 102 displayed similar potencies with IC₅₀

values of 124 and 146 nm, respectively; a twofold loss of activi-

ty relative to the N-methylbenzamide 52 with the ethanone

ether linker. However, with highly polarised linkers like the sulf-

oxide 103 or the sulfone 104 in the N,N-dimethylbenzamide

series, compounds regained activity to give the most potent

compounds in this series with IC₅₀values of ~60–70 nm, which

indicates that a sulfone or sulfoxide unit of the linker is form-

ing further interactions with the active site.

Table 3. In vitro inhibitory activity of 4-benzamide derivatives.

Compd

R¹

R²

IC₅₀[nm]

42

43

44

45

46

47

48

49

50

H

Et

H

Me

Et

iPr

tBu

Et

Ph

Bn

117

63%^[a]

382

594

1140

798

283

1959

69%^[a]

2-Furfuryl

[a] Percent inhibition measured at a concentration of 1 mm.

Table 4. In vitro inhibitory activity of 3-benzamide derivatives.

Compd

X

R¹

R²

IC₅₀[nm]

51

52

O

H

Me

1047

68

Replacement of the carboxamide with the acetamide group

gives extra flexibility to the side chain. In the para-acetamide

series, the IC₅₀value of the N-methyl substituted compound

(61) was 94 nm (Table 5), much more potent than the para-car-

boxamide analogue 43 and similar to the meta analogue 52,

suggesting the extra flexibility may enable the methyl group

to reach a binding region like the meta substituent. The ex-

tended acetamide compounds are able to interact with the

enzyme in a fashion similar to the previously described carbox-

amide family. The potent activity of the N,N-dimethylacetamide

62 (IC₅₀=58 nm) indicates that a hydrogen-bond donor at-

tached to the phenyl ring is not required for activity, and the

combination of the amide carbonyl acting as a hydrogen-bond

acceptor and the N,N-dimethyl substituent being able to pick

up added hydrophobic interactions improves potency. The

nonsubstituted acetamide 63 showed a decreased activity

with an IC₅₀value of 204 nm possibly due to some loss of hy-

drophobic binding with the enzyme. Bulky alkyl substituents

are not well tolerated with the N-ethyl compound (64) losing

activity by approximately fourfold and the isopropyl (65) and

tert-butyl compounds (66) showing weaker inhibition as previ-

ously observed with enlarged steric bulk (compounds 44–46 in

Table 3 and 53–55 in Table 4). Some aromatic interactions with

53

54

55

56

57

58

101

102

103

104

O

S

H

Me

Et

iPr

tBu

2-Furfuryl

Bn

343

1222

59%^[a]

229

527

876

124

146

57

Ph

Me

SO

SO₂

Me

69

[a] Percent inhibition measured at a concentration of 1 mm.

acetamides with an ethanone linker (Table 5) and para-benza-

mides with an extra methylene unit in the linker (Table 6).

Interestingly, we discovered that the nonsubstituted para-

benzamide 42 had an IC₅₀value of 117 nm, while alkyl-substi-

tuted compounds like the methyl (43), ethyl (44), isopropyl

(45) or tert-butyl (46) derivatives all showed lower activity, indi-

cating that a bulky alkyl group in this region is not well tolerat-

ed (Table 3). This is also true for the N,N-diethylbenzamide

compound (47) with an IC₅₀value of 798 nm. The N-phenylcar-

boxamide derivative (48) gave an interesting IC₅₀value of

1030

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

To establish the structure–activity relationships of the ada-

mantyl ethanone derivatives with various substituents on the

phenyl ring, compounds substituted with the carboxylic acid

and their corresponding methyl esters were tested. The free

acid group may facilitate the aqueous solubility of these hy-

drophobic molecules. In the adamantyl ethanone ether series

(Table 7), it was found that a carboxylic acid group at the para

Table 5. In vitro inhibitory activity of 4-phenylacetamide derivatives.

Compd

R¹

R²

IC₅₀[nm]

61

62

63

64

65

66

67

68

69

H

Me

H

Me

H

Et

iPr

94

58

204

912

Table 7. In vitro inhibitory activity of phenyl or benzyl carboxylic acids or

esters.

63%^[a]

45%^[a]

472

tBu

Bn

Ph

2-Furfuryl

2194

4%^[a]

[a] Percent inhibition measured at a concentration of 1 mm.

Compd

R

n

IC₅₀[nm]

23

40

24

41

25

59

32

60

p-COOMe

p-COOH

m-COOMe

m-COOH

p-CH₂COOMe

p-CH₂COOH

p-COOMe

p-COOH

0

1

25%^[a]

74

78

153

2580

400

55%^[a]

359

the enzyme may be present as the benzyl derivative (67) had

an IC₅₀value of 472 nm, whereas the phenyl (68) and 2-furfuryl

compounds (69) lost activity indicating that the size and posi-

tion of the aromatic group in the active site are important for

activity.

[a] Percent inhibition measured at a concentration of 1 mm.

The flexibility of the linker was also modified by adding an

extra methylene group between the oxygen and the phenyl

ring. A trend similar to that in the phenylacetamide series was

observed (Table 6). The unsubstituted carboxamide 70 and the

position, as in compound 40 (IC₅₀=74 nm), is much more

potent than the corresponding methyl ester analogue 23 (25%

at 1 mm). However, upon moving the methyl ester to the meta

position to give compound 24, the activity is regained with an

IC₅₀value of 78 nm. This is in agreement with the finding in

the benzamide series where hydrophobic interactions are pre-

ferred in the meta position. The free acid analogue 41 was

twofold less potent than 24 and retained activity with an IC₅₀

value of 153 nm. However, extending the chain length to give

added flexibility, as in compounds 25 and 59, or extra flexibility

in the linker (i.e., compounds 32 and 60) did not improve the

activity. The two free acid derivatives 59 and 60 with extended

side chains exhibited moderate inhibition of 11b-HSD1 with

IC₅₀values in the 300–400 nm range.

Table 6. In vitro inhibitory activity of 4-benzamide derivatives.

Compd

R¹

R²

IC₅₀[nm]

70

71

72

73

H

Me

H

63%^[a]

250

56

69%^[a]

Me

Bn

[a] Percent inhibition measured at a concentration of 1 mm.

The effects of hydrophobic substituents with different size

and electronic properties on the phenyl ring were investigated

(Table 8 and Table 9). Compounds with an ethanone ether

linker attached directly to the phenyl ring gave only moderate-

ly active compounds in the mid to low micromolar range irre-

spective of the size and electronic properties of the substitu-

ents (Table 8). With a sulfide, sulfoxide or sulfone linker in com-

bination with a series of para-substituents in the phenyl ring,

moderate inhibition of 11b-HSD1 was observed (Table 8). Com-

pounds with nanomolar activity included the para-chloro-sul-

fide-linked analogue 76, the para-methyl-sulfoxide derivative

86 and the para-methyl-sulfone 94, with IC₅₀values of 810 nm,

443 nm and 668 nm, respectively.

N-benzyl compound 73 showed weaker activities, which might

indicate that the lack of hydrophobic or aromatic interactions

in this region has negative effects on the inhibitory activity. On

the other hand the activity of the N-methyl compound (71),

with an IC₅₀value of 250 nm, indicates that hydrophobic inter-

actions limited to a confined region are preferred. Further-

more, the combination of the extended ethanone linker and

phenyl N,N-dimethylcarboxamide to give derivative 72 provid-

ed the most potent compound in this series with an IC₅₀value

of 56 nm. This result clearly shows that an N,N-dimethylamide

moiety in combination with the appropriate linker to the ada-

mantyl ketone is able to inhibit 11b-HSD1 with high potency

as compounds containing this group including 103, 104, 62

and 72, all have IC₅₀values <70 nm.

Considering the more flexible ethanone ether linker contain-

ing an extra methylene unit, it was discovered that the majori-

ty of compounds with hydrophobic or aromatic substitutions

on the phenyl ring only exhibited weak inhibition of 11b-HSD1,

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1031

B. V. L. Potter et al.

MED

pounds with bulky alkyl substituents in the phenyl ring were

only weakly active at inhibiting 11b-HSD1. The para-chloro-

phenyl derivative 87, with a sulfoxide linker, had an activity six-

fold greater than the analogous shorter linker compound 85,

and was a potent inhibitor. The ortho-para-dichlorophenyl sul-

fone 99 also exhibited high activity with an IC₅₀value of

171 nm. The most active compounds in these series are 88

(IC₅₀=122 nm) and 96 (IC₅₀=128 nm), with an ortho-chloro

substituent on the phenyl ring and a longer ethanone sulfox-

ide or sulfone linker, respectively. These are novel, potent in-

hibitors of 11b-HSD1. The above results indicate that the sulf-

oxide and sulfone linkers may not only change the geometry

of the molecule, but may also interact as hydrogen-bond ac-

ceptors with amino acid residues in the active site of 11b-

HSD1. Both of these effects would improve the binding of the

compounds to 11b-HSD1 through hydrophobic and a network

of hydrogen bonding interactions. The results from Tables 8

and 9 indicate that, with the appropriate linker and substitu-

tion in the phenyl ring in these adamantyl ketone series,

potent inhibition of 11b-HSD1 can be achieved.

Table 8. In vitro inhibitory activity of benzene derivatives.

Compd

X

R

IC₅₀[nm]

26

27

28

29

30

31

76

77

85

86

93

94

O

S

SO

SO₂

p-Ph

p-CF₃

m-CF₃

p-Cl

p-Me

m,p-di-OMe

p-Cl

4900

5236

46%^[a]

1000

2510

9379

810

6720

1438

443

56%^[a]

668

p-Me

p-Cl

p-Me

p-Cl

p-Me

[a] Percent inhibition measured at a concentration of 1 mm.

especially for compounds with substituents such as phenyl

and trifluoromethyl (compounds 33, 34, 35; Table 9). However,

the para-methoxy and meta-para-dimethoxy derivatives 37

and 38 showed good inhibition of 11b-HSD1 with IC₅₀values

around 300 nm. When replacing the ether linker with a thioeth-

er, as in compounds 78–82, only weak inhibition of 11b-HSD1

was achieved.

Selected compounds from the adamantyl ethanone series

were also tested for their selectivity towards 11b-HSD2 and

17b-HSD1, and the results indicated that they did not inhibit

these enzymes.

Metabolic stability and CYP450 inhibition studies

However, when the ethanone ether linker was replaced with

ethanone sulfoxide or sulfone, as in compounds 88–99, some

interesting activities were observed. Again, in general, com-

A selection of potent compounds (62, 72, 92 and 103), with

IC₅₀values in the 50–70 nm range, was evaluated on human

liver microsomes in order to determine their metabolic stabili-

ty. The results shown in Table 10 represent the remaining

Table 9. In vitro inhibitory activity of substituted benzene derivatives

with an extended linker.

Table 10. Metabolism studies in human liver microsomes.^[a]

t ₌[min] CL_int[mLmin^ꢀ1mg^ꢀ1

]

Metabolites^[c]

1

Compd

Remaining

compd [%]^[b]

2

62

72

92

87

11

50

67

59

11

27

9.5

11

73

24

0

4

2

Compd

X

R

IC₅₀[nm]

33

34

35

36

37

38

39

78

79

80

81

82

87

88

89

90

95

96

97

98

99

O

S

p-Ph

p-CF₃

m-CF₃

p-Me

p-OMe

m,p-di-OMe

p-Cl

o-Cl

m-Me

p-tBu

o,p-di-Cl

p-Cl

38%^[a]

35%^[a]

31%^[a]

2069

296

103

[a] The parent compound was incubated at 378C with human liver micro-

somes in the presence of the cofactor NADPH for 40 min. Evaluation of

disappearance of parent compound and identification of metabolites was

performed using HPLC. [b] The amount of compound remaining after

30 min. [c] The number of metabolites detected.

339

53%^[a]

74%^[a]

24%^[a]

26%^[a]

68%^[a]

231

S

quantity of each compound after 30 min incubation, the half-

life, the intrinsic clearance and the number of metabolites, as

measured by HPLC.

SO

SO₂

o-Cl

122

p-tBu

o,p-di-Cl

p-Cl

60%^[a]

2975

1350

128

Compound 92, with an ethanone sulfone linker attached to

the 4-acetamidophenyl group, was rapidly metabolised, with

only 11% of the original compound left after 30 min, and had

a half-life of 11 min; four metabolites were detected by HPLC.

The clearance rate of this compound is also high at

73 mLmin^ꢀ1mg^ꢀ1. Compound 103, with an ethanone sulfoxide

linker, exhibited improved metabolic stability relative to 92,

o-Cl

m-Me

p-tBu

o,p-di-Cl

45%^[a]

2017

171

[a] Percent inhibition measured at a concentration of 1 mm.

1032

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

with 50% of the compound remaining after 30 min. However,

with a half-life of <30 min, two metabolites detected from the

microsomal incubation

and

a

clearance

rate of

24 mLmin^ꢀ1mg^ꢀ1, this compound is metabolised relatively

quickly. On the other hand, compounds 62 and 72, with an

ethanone ether linker, displayed greatly enhanced metabolic

stability with ~90% of the compound remaining after 30 min

incubation, no metabolites detected by HPLC, a half-life of 1 h

and an intrinsic clearance of ~10 mLmin^ꢀ1mg^ꢀ1. These results

show that, with the combination of a suitable linker and

phenyl acetamide or benzamide substitution, the adamantyl

ketone group in 62 and 72 is resistant to metabolism. These

compounds show properties worthy of further preclinical stud-

ies.

Figure 1. Superimposition of inhibitors and NADP(H) from fourteen human

11b-HSD1 crystal structures.

pocket. The atoms to the left of the line are on the surface of

the protein exposed to the surrounding solvent.

Based on their inhibitory activity against 11b-HSD1 and

other properties, compounds 62, 72 and 103 were selected,

and their inhibition of key human cytochrome P450 enzymes

(1A2, 2C9, 2C19, 2D6, 3A4-BFC and 3A4-BQ) was examined

(Table 11). Compound 72 showed only very weak inhibitory ac-

Figure 2 shows the main chain atoms of the walls of the

substrate binding site, but not the atoms at the base of the

pocket containing the catalytic residues. For clarity, only the

Table 11. Inhibition of human cytochrome P450 enzymes.

CYP450

Compd

72 (IC₅₀[mm])

62 [%]^[a]

103 [%]^[a]

1A2

2C9

2C19

2D6

3A4-BFC

3A4-BQ

0

93

83

0

92

51

>100

20

>100

22

0

71

0

100

40

86

[a] Percent inhibition measured at a concentration of 10 mm.

tivity against all CYP450 enzymes used in the assay, with IC₅₀

values of >100 mm (1A2), >100 mm (2C9), 20 mm (2C19),

>100 mm (2D6), 22 mm (3A4-BFC) and 86 mm (3A4-BQ). Al-

though showing no inhibition for 1A2 and 2D6, 62 exhibited

some inhibition at a concentration of 10 mm for 2C9 (93%),

2C19 (83%), 3A4-BFC (92%) and 3A4-BQ (51%). Similarly, com-

pound 103 also showed some inhibition at a concentration of

10 mm for 2C19 (71%), 3A4-BFC (100%) and 3A4-BQ (40%).

Compound 72 has the best overall profile on both metabolic

stability and CYP inhibition.

Figure 2. Superimposition of binding site residues of 11b-HSD1 crystal struc-

tures.

backbone atoms of the superimposed structures are depicted

to demonstrate the backbone variability. Looking from the sur-

face of the protein into the substrate binding site, residues

Ala223–Ala236 on the right and Lys174–Val180 on the left

form the walls of the binding site. If these two walls of the

binding site are static, access to the space between the two

walls is limited, and it is unlikely that an inhibitor would be

able to access the cortisone binding pocket. However, as

shown by the variable conformation of the wall on the right,

the two walls of the pocket are probably hinged so that they

are able to move apart to allow the cortisone (or inhibitor)

into the pocket. This flexibility suggests that bulkier inhibitors

may be accommodated in the binding site. 2-(N-Morpholino)-

ethanesulfonic acid (MES; buff-coloured molecule in Figures 1

and 2) does not lie in the substrate binding site; it is not an in-

hibitor but a molecule from the crystallisation buffer that lies

on the surface of the protein. This shows that inhibitors may

Molecular modelling: docking studies

Fourteen of the publicly available crystal structures of human

11b-HSD1 (1XU7,^[49]1XU9,^[49]2BEL, 2ILT,^[43]2IRW,^[50]2RBE,^[51]

3BYZ,^[52]3BZU,^[53]3CH6,^[54]3CZR,^[55]3D3E,^[56]3D4N,^[56]3D5Q,^[57]

3EY4^[44]and 3FRJ^[58]) were superimposed to determine the

shape, volume and flexibility of the substrate binding site. The

NADP(H) molecules from all fourteen structures were found to

be superimposable—the different inhibitors have little influ-

ence on the structure of the protein around the NADP(H). In

Figure 1, all the inhibitor atoms to the right of the vertical

black line are in the hydrophobic cortisone (substrate) binding

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1033

B. V. L. Potter et al.

MED

be able to exploit the area occupied by this molecule to in-

crease potency or selectivity and solubility.

bonyl group that forms a hydrogen bond acceptor interaction

with Ser170, 2.87 ꢁ away. In both cases, the carbonyl moiety

of the acetamide group can accept a hydrogen bond from the

backbone NH of Leu217 being 2.36 ꢁ and 2.39 ꢁ away from

102 and 104, respectively.

The effects of the N-methylacetamide side chain of 61 or

the N-dimethylacetamide of 62 on the proposed binding

mode of the molecules were studied (Figure 4). Both ligands

To evaluate which X-ray crystal structure is the most suitable

for use in docking studies for our ligands, cortisone and com-

pound 62 were docked, using the GOLD docking program

(version 4.1), into all fourteen crystal structures in the presence

of the cofactor. Based on the docked poses and the docking

scores, we found that the 2ILT, 2IRW and 3CH6 structures were

the most suitable for docking studies using our current phar-

macophore. The identification of the 2ILT and 2IRW structures

as suitable for docking studies was not too surprising as both

contain a ligand with a bulky adamantyl group. However, the

reason the 3CH6 structure was identified is less clear; in terms

of the structure of the substrate binding site, it is very similar

to the 2ILT and 2IRW structures. Ligands from the adamantyl

ethanone series were chosen and docked into the 2ILT crystal

structure with the binding site 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 func-

tion was used to rank the ligands in order of fitness.

Figure 3 shows the best docking solutions for both com-

pound 102 and 104; these predicted binding conformations

have the adamantyl part close to the nicotinamide group of

Figure 4. Docking solutions of compounds 61 (in cyan) and 62 (in buff).

are predicted to bind in a way that orients the adamantyl

group towards the cofactor, but the direction of the acetamide

moiety differs slightly between the two, with the amide car-

bonyl groups pointing in different directions. The dimethylace-

tamide moiety of 62 occupies a hydrophobic pocket formed

by residues Leu217, Val231 and Met233. The methyl group of

the methylacetamide of 61 also fits into this pocket, but the

rotation of the carbonyl enables the methylacetamide NH

group to form an added hydrogen bond to Asp259, 3.67 ꢁ

away. The carbonyl moiety in both compounds 61 and 62,

being a distance of 2.25 ꢁ and 2.43 ꢁ, respectively, from the

catalytic Tyr183 residue, are likely able to act as hydrogen-

bond acceptors. In addition, the ether oxygen in the linker in

both compounds 61 and 62 can form a similar hydrogen-bond

acceptor interaction with Ser170 in the active site, being

3.00 ꢁ and 2.67 ꢁ away from this residue, respectively.

Figure 3. Docking solutions for compounds 102 (in cyan) and 104 (in buff).

the cofactor, fitting tightly into the lipophilic pocket, which is

made up of the residues Leu126, Ile230, Val227, Leu217,

Ala223 and Val180. The ketone moiety of compound 104

forms a hydrogen bond with the catalytic residue Tyr183,

which is 2.5 ꢁ away. Furthermore, the bridging sulfone group

is also in a good position to accept hydrogen bonds from

Ser170 with either oxygen at distances of 2.33 ꢁ and 2.40 ꢁ

away as depicted. In addition, Leu171 and Ala172, being

2.97 ꢁ and 3.07 ꢁ, respectively, away from a sulfone oxygen of

104, may also form hydrogen bonding interactions. For com-

pound 102, it is the bridging sulfur atom rather than the car-

With the extended linker system, compound 71 showed

some interesting docking modes (Figure 5). The highest scor-

ing solution of 71 does not orient the adamantyl group in the

same way as the other ligands examined here. In this proposed

binding mode, the adamantyl group is positioned away from

the cofactor, and the phenyl ring sits in the hydrophobic

pocket near NADP. However, the fourth best solution for 71

has the ’normal’ orientation, that is, with the adamantyl group

positioned near the cofactor. Compound 71 is 4.5 times less

active than 72 and the possibility that this ligand could adopt

1034

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

Experimental Section

General methods

All chemicals were purchased from either Aldrich Chemical Co. (Gil-

lingham, 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 Stanford Research Sys-

tems Optimelt and are uncorrected. Target compounds in solid

form were crystallised from CH₂Cl₂/EtOAc. Thin layer chromatogra-

phy (TLC) was performed on precoated aluminium plates (Merck,

silica gel 60 F₂₅₄). Product spots were visualised either by UV irradi-

ation at 254 nm and by staining with 5% w/v molybdophosphoric

acid in EtOH, followed by heating. Flash column chromatography

was performed on prepacked columns (Isolute) and gradient elu-

tion (solvents indicated in text) on a Flashmaster II system (Biot-

age). ¹H NMR spectra were recorded with a Jeol Delta 270 MHz.

Chemical shifts (d) are reported in parts per million (ppm) relative

to tetramethylsilane (TMS) as an internal standard. LC–MS spectra

were performed 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 mLmin^ꢀ1), and detected with a ZQ MicroMass spec-

trometer and PDA detector using Atmospheric Pressure Chemical

Ionisation (APCI) or Electrospray Ionisation (ESI). High resolution

mass spectra were recorded on a Bruker MicroTOF with ESI or at

the EPSRC National Mass Spectrometry service, Swansea with the

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 (pack-

ing: 3.5 mm, 4.6 mm ꢂ 150 mm) with an isocratic mobile phase

Figure 5. Docking solutions of compounds 71 (in cyan) and 72 (in buff).

two different binding modes could play a part in this. The di-

methylacetamide moiety in 72 could play a role in helping the

ligand lock itself into this specific binding mode by fitting

comfortably into a pocket formed by Leu126, Pro178, Met179,

Val180, Val227, Val231 and Met233. In this orientation, the

phenyl ring stacks with the ring of Tyr177 at a distance of

3.15 ꢁ.

Conclusions

consisting of H₂O/CH₃CN with a flow rate of 1.0 mLmin^ꢀ1

.

In summary, we report the discovery of adamantyl ethanone

derivatives as novel, potent, inhibitors of human 11b-HSD1. A

number of compounds were identified with IC₅₀values in the

range of 50–70 nm when evaluated on a HEK-293 cell line

stably transfected with the HSD11B1 gene. Potent compounds

in these novel series are inactive on human 11b-HSD2 and se-

lected compounds are also inactive on human 17b-HSD1.

The structure–activity relationship studies indicate that an

adamantyl ethanone tethered to a substituted phenyl ring

through an oxygen, sulfur, sulfoxide or sulfone linker consti-

tutes a suitable pharmacophore for the inhibition of human

11b-HSD1. The linker geometry, side chain size and orientation

play a key role in determining the inhibitory properties of the

molecules. Molecular modelling of the potent compounds

using a crystal structure of human 11b-HSD1 predicted how

these molecules may interact with the enzyme and cofactor.

The ketone group in the linker is proposed to play a key role,

interacting with residues Tyr183 and Ser170 in the catalytic

region. The mechanistic study from Wyeth suggested that a

known 11b-HSD1 inhibitor with a b-keto sulfone linker is a sub-

strate of the enzyme.^[59]Our compounds with a ketone group

in the same approximate region may also act as substrates;

however, we have not tested this hypothesis.

11b-HSD1 scintillation proximity assay (SPA) protocol:

human cell based assay^[60]

Nontransfected HEK293 cells lack endogenous 11b-HSD1 activity,

and this cell line has been shown to be a suitable system for evalu-

ating 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 tritiated product by

using a scintillation proximity assay (SPA). The high-throughput

cell-based assays were conducted on the human 11b-HSD1 trans-

fected HEK293 cell line with an SPA. The activity of 11b-HSD1 was

measured in whole HEK293 cells stably transfected with the

HSD11B1 gene using modified literature protocols. Cells were incu-

bated in 96-well microplates in the presence of tritiated substrate,

and the assay plates contained internal high and low controls to

allow calculation of the percent 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 re-

moved from each well and then 100 mL of fresh, serum-free,

medium containing [³H]cortisone and test compound in 1% DMSO

were added to each well. The control wells were also dispensed.

The high control wells did not contain compound, while low con-

trols 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 microplate containing 100 mL

of a pre-incubated 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.

The most potent compound, 72, exhibited an IC₅₀value of

56 nm for 11b-HSD1 and was metabolically stable upon human

liver microsomal incubation with a half-life of 59 min and an

intrinsic clearance of 11 mLmin^ꢀ1mg^ꢀ1. Furthermore, com-

pound 72 showed very weak activity against key human

CYP450 enzymes and therefore is regarded as a candidate

worthy of further preclinical investigation.

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1035

B. V. L. Potter et al.

MED

ture was stirred at RT under nitrogen, and monitored by TLC. After

completion, the mixture was partitioned between EtOAc and brine.

The organic phase was washed with brine, dried over Na₂SO₄and

concentrated in vacuo to give the crude product. Purification using

flash chromatography (hexane/EtOAc or CH₂Cl₂/EtOAc; gradient

elution) yielded the target compound (yield 37–100%).

Docking study procedure

Selected ligands were docked into the 11b-HSD1 protein X-ray

crystal structure (PDB: 2ILT) using the GOLD docking program, ver-

sion 4.1 with default settings 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 crystal structure. Each ligand was

docked 25 times. The GoldScore scoring function was used to rank

the ligands in order of fitness.

1-Adamantan-1-yl-2-(2-methylbenzothiazol-5-yloxy)ethanone

(15): A white solid (341 mg, 100%); mp: 123–124.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.71–1.79 (6H, m), 1.93 (brd, J=3.0 Hz, 6H),

2.04–2.11 (m, 3H), 2.78 (s, 3H), 4.94 (s, 2H), 7.04 (dd, J=8.8, 2.5 Hz,

1H), 7.28 (d, J=2.5 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H); LC–MS (APCI)

m/z: 342.4 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₄NO₂S:

342.1522, found: 342.1521; HPLC: t_R=18.7 min (>99%) in 30%

H₂O/CH₃CN.

Method A: Synthesis of ethanone amino linker compounds

11–14

A solution of aryl bromomethyl ketone or 1-adamantyl bromo-

methyl ketone (1 mmol) in ethanol or CH₃CN (10 mL) was treated

with K₂CO₃(100 mg), followed by the corresponding amine

(1 mmol). The mixture was stirred at RT under nitrogen, and moni-

tored by TLC. After completion, the mixture was partitioned be-

tween EtOAc and 5% aq NaHCO₃. The organic phase was washed

with brine, dried over Na₂SO₄and concentrated in vacuo to give

the crude product. Purification using flash chromatography

(hexane/EtOAc; gradient elution) yielded the target compound

(yield 40–70%).

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]acetamide (16):

A

white crystalline solid (281 mg, 86%); mp: 177–1788C; ¹H NMR

(270 MHz, CDCl₃): d=1.66–1.82 (m, 6H), 1.90 (d, J=2.7 Hz, 6H),

2.07 (brs, 3H), 2.13 (s, 3H), 4.82 (s, 2H), 6.80 (dt, J=8.9, 2.2 Hz,

2H), 7.13 (brs, 1H), 7.36 (dt, J=9.0, 2.3 Hz, 2H); LC–MS (APCI) m/z:

326 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+Na]⁺calcd for C₂₀H₂₅NO₃Na:

350.1732, found: 350.1720; HPLC: t_R=2.45 min (>99%) in 10%

H₂O/CH₃CN.

N-[3-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]acetamide (17):

A

1-(4-Chlorophenyl)-2-(2-methylbenzo[d]thiazol-5-ylamino)etha-

none (11): A light yellow solid (90 mg); mp: 172–1748C; ¹H NMR

(270 MHz, CDCl₃): d=2.79 (s, 3H), 4.64 (d, J=4.5 Hz, 2H), 5.00 (t,

J=4.4 Hz, 1H), 6.83 (dd, J=8.6, 2.2 Hz, 1H), 7.18 (d, J=2.2 Hz, 1H),

7.50 (dt, J=8.6, 1.8 Hz, 2H), 7.59 (d, J=8.7 Hz, 1H) and 7.96 (dt,

J=8.4, 1.8 Hz, 2H); LC–MS (APCI) m/z: 315 [MꢀH]^ꢀ; HRMS (FAB)

m/z [M+H]⁺calcd for C₁₆H₁₄ClN₂OS: 317.0515, found: 317.0504;

HPLC: t_R=2.52 min (98%) in 20% H₂O/CH₃CN.

white solid (300 mg, 92%); mp: 136–1378C; ¹H NMR (270 MHz,

CDCl₃): d=1.68–1.79 (m, 6H), 1.91 (d, J=2.7 Hz, 6H), 2.06 (brs,

3H), 2.15 (s, 3H), 4.86 (s, 2H), 6.63 (dd, J=8.3, 2.2 Hz, 1H), 6.90 (dd,

J=8.2, 2.2 Hz, 1H), 7.14–7.20 (m, 2H), 7.30 (t, J=2.7 Hz, 1H); LC–

MS (ESI) m/z 326 [MꢀH]^ꢀ; HRMS (ESI) m/z [M+Na]⁺calcd for

C₂₀H₂₅NO₃Na: 350.1732, found: 350.1704; HPLC: t_R=2.18 min (99%)

in 10% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)-2-methyl-phenyl]aceta-

mide (18): An off-white amorphous solid (158 mg, 46%); mp: 201–

2048C; H NMR (270 MHz, CDCl₃): d=1.68–1.82 (m, 6H), 1.90 (d, J=

2.7 Hz, 6H), 2.07 (brs, 3H), 2.16 (s, 3H), 2.20 (s, 3H), 4.80 (s, 2H),

6.65 (dd, J=8.8, 2.9 Hz, 1H), 6.72 (d, J=3.0 Hz, 1H), 6.83 (brs, 1H),

7.17 (d, J=8.7 Hz, 1H); LC–MS (APCI) m/z: 340 [MꢀH]^ꢀ; HRMS

(FAB) m/z [M+Na]⁺calcd for C₂₁H₂₇NO₃Na: 364.1889, found:

364.1868; HPLC: t_R=1.78 min (99%) in 10% H₂O/CH₃CN.

1-(2,4-Dichlorophenyl)-2-(2-methylbenzo[d]thiazol-5-ylamino)-

ethanone (12): A yellow solid (168 mg); mp: 125–1278C; H NMR

1

(270 MHz, CDCl₃): d=2.78 (s, 3H), 4.61 (brs, 2H), 4.91 (brs, 1H),

6.78 (dd, J=8.8, 2.6 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.36 (dd, J=

8.4, 2.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H) and

7.67 (d, J=8.4 Hz, 1H); LC–MS (APCI) m/z: 349 [MꢀH]^ꢀ; HRMS

(FAB) m/z [M+H]⁺calcd for C₁₆H₁₃Cl₂N₂OS: 351.0126, found:

351.0109; HPLC: t_R=2.58 min (98%) in 20% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)-2-chloro-phenyl]acetamide

(19): A white solid (280 mg, 77%); mp: 204–2068C; ¹H NMR

(270 MHz, CDCl₃): d=1.65–1.80 (m, 6H), 1.90 (d, J=2.8 Hz, 6H),

2.07 (brs, 3H), 2.20 (s, 3H), 4.81 (s, 2H), 6.76 (dd, J=9.0, 3.0 Hz,

1H), 7.24 (d, J=2.9 Hz, 1H), 7.38 (brs, 1H), 8.17 (d, J=9.0 Hz, 1H);

LC–MS (APCI) m/z: 360 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+Na]⁺calcd

for C₂₀H₂₄ClNO₃Na: 384.1342, found: 384.1320; HPLC: t_R=1.92 min

(99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(2-methylbenzothiazol-5-ylamino)ethanone

(13): An off-white solid (185 mg); mp: 133–1368C; ¹H NMR

(270 MHz, CDCl₃): d=1.69 (m, 6H), 1.84 (d, J=2.7 Hz, 6H), 2.02

(brs, 3H), 2.71 (s, 3H), 4.06 (s, 2H), 4.75 (brs, 1H), 6.68 (dd, J=8.6,

2.4 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H); LC–MS

(APCI) m/z: 341 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₀H₂₅N₂OS: 341.1687, found: 341.1683; HPLC: t_R=3.53 min (99%)

in 20% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)-3-chloro-phenyl]acetamide

(20): A white solid (330 mg, 91%); mp: 227–228.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.68–1.78 (m, 6H), 1.91 (d, J=2.7 Hz, 6H),

2.00 (brs, 3H), 2.14 (s, 3H), 4.89 (s, 2H), 6.53 (d, J=8.9 Hz, 1H),

7.15 (brs, 1H), 7.31 (dd, J=8.9, 2.7 Hz, 1H), 7.49 (d, J=2.8 Hz, 1H);

LC–MS (APCI) m/z: 360 [MꢀH]^ꢀ; HRMS (ESI) m/z [M+Na]⁺calcd for

C₂₀H₂₄ClNO₃Na: 384.1342, found: 384.1328; HPLC: t_R=2.22 min

(>99%) in 10% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethylamino)phenyl]acetamide (14):

A white solid (222 mg); mp: 156–1588C; H NMR (270 MHz, CDCl₃):

1

d=1.66–1.75 (m, 6H), 1.87 (d, J=2.8 Hz, 6H), 2.07 (brs, 3H), 2.12

(s, 3H), 4.04 (s, 2H), 4.63 (brs, 1H), 6.57 (dd, J=7.1, 1.9 Hz, 2H),

6.99 (brs, 1H), 7.28 (dd, J=7.2, 1.9 Hz, 2H); LC–MS (APCI) m/z: 327

[M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₇N₂O₂327.2073,

found: 327.2075; HPLC: t_R=4.93 min (98%) in 10% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)-2-fluoro-phenyl]acetamide

(21): A white solid (230 mg, 67%); mp: 191–192.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.65–1.80 (m, 6H), 1.90 (d, J=2.8 Hz, 6H),

2.07 (brs, 3H), 2.18 (s, 3H), 4.81 (s, 2H), 6.55–6.70 (m, 2H), 7.14

(brs, 1H), 8.08 (t, J=8.9 Hz, 1H); LC–MS (APCI) m/z: 344 [MꢀH]^ꢀ;

Method B: Synthesis of ethanone ether linker compounds

15–31

A solution of 1-adamantyl bromomethyl ketone (257 mg, 1 mmol)

in acetone or DMF (10 mL) was treated with K₂CO₃(276 mg,

2 mmol), followed by the corresponding phenol (1 mmol). The mix-

1036

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

HRMS (FAB) m/z [M+Na]⁺calcd for C₂₀H₂₄FNO₃Na: 368.1638,

found: 368.1619; HPLC: t_R=1.79 min (99%) in 10% H₂O/CH₃CN.

J=9.0, 2.2 Hz, 2H); LC–MS (APCI) m/z: 305 [M+H]⁺; HRMS (FAB)

m/z [M+H]⁺calcd for C₁₈H₂₂ClO₂: 305.1308, found: 305.1299;

HPLC: t_R=2.41 min (>99%) in 4% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethoxy)-3-methyl-phenyl]aceta-

1

mide (22): A white solid (255 mg, 75%); mp: 201–202.58C; H NMR

1-Adamantan-1-yl-2-p-tolyloxy-ethanone (30): A white crystalline

1

(270 MHz, CDCl₃): d=1.58–1.75 (m, 6H), 1.91 (d, J=2.7 Hz, 6H),

2.06 (brs, 3H), 2.13 (s, 3H), 2.26 (s, 3H), 4.82 (s, 2H), 6.54 (d, J=

8.7 Hz, 1H), 7.02 (brs, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.7,

2.5 Hz, 1H); LC–MS (APCI) m/z: 340 [MꢀH]^ꢀ; HRMS (ESI) m/z

[M+H]⁺calcd for C₂₁H₂₈NO₃: 342.2069, found: 342.2052; HPLC: t_R=

2.89 min (99%) in 30% H₂O/CH₃CN.

solid (244 mg, 86%); mp 90–918C; H NMR (300 MHz, CDCl₃): d=

1.71–1.83 (m, 6H), 1.93 (d, J=2.7 Hz, 6H), 2.09 (brs, 3H), 2.28 (s,

3H), 4.83 (s, 2H), 6.78 (dt, J=8.9, 2.0 Hz, 2H), 7.09 (dt, J=8.8,

2.0 Hz, 2H); LC–MS (APCI) m/z: 285 [M+H]⁺; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₅O₂: 285.1855, found: 285.1849; HPLC: t_R=

2.44 min (>99%) in 4% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)benzoic acid methyl ester

(23): A white solid (122 mg, 37%); mp: 128–1298C; ¹H NMR

(270 MHz, CDCl₃): d=1.68–1.83 (m, 6H), 1.91 (d, J=2.7 Hz, 6H),

2.08 (brs, 3H), 3.87 (s, 3H), 4.90 (s, 2H), 6.85 (dt, J=9.1, 2.7 Hz,

2H), 7.96 (dt, J=8.9, 2.7 Hz, 2H); LC–MS (APCI) m/z: 329 [M+H]⁺;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₅O₄: 329.1747, found:

329.1736; HPLC: t_R=2.39 min (98%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(3,4-dimethoxy-phenoxy)ethanone (31): A

1

white crystalline solid (278 mg, 84%); mp: 113.5–114.58C; H NMR

(270 MHz, CDCl₃): d=1.69–1.79 (m, 6H), 1.90 (d, J=2.8 Hz, 6H),

2.07 (brs, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 4.79 (s, 2H), 6.27 (dd, J=

8.9, 3.0 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H); LC–

MS (APCI) m/z: 331 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₀H₂₇O₄: 331.1909, found: 331.1902; HPLC: t_R=3.15 min (>99%)

in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)benzoic acid methyl ester

(24):

A

white solid (326 mg, 99%); mp: 84–858C; ¹H NMR

(270 MHz, CDCl₃): d=1.68–1.82 (m, 6H), 1.92 (d, J=2.9 Hz, 6H),

2.08 (brs, 3H), 3.89 (s, 3H), 4.90 (s, 2H), 7.11 (ddd, J=8.4, 2.7,

1.0 Hz, 1H), 7.33 (t app, J=7.9 Hz, 1H), 7.46 (dd, J=2.7, 1.5 Hz,

1H), 7.63 (dt, J=6.5, 1.2 Hz, 1H); LC–MS (APCI) m/z: 327 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₅O₄: 329.1747, found:

329.1746; HPLC: t_R=3.05 min (>99%) in 10% H₂O/CH₃CN.

Method C: Synthesis of ethanone ether linker compounds

32–37

A suspension of NaH (60% in mineral oil, 1.1 equiv) in dry THF was

treated with the alcohol (1.0 equiv) at 08C. After stirring for 30 min

at 08C, 1-adamantyl bromomethyl ketone (1.1 equiv) was added in

dry THF. The reaction was stirred for 2 h at 08C then allowed to

warm to RT overnight. After quenching with water, the mixture

was extracted twice with Et₂O, washed with water then brine,

dried over MgSO₄, and then concentrated in vacuo. The crude

product was purified using flash chromatography (hexane/EtOAc

or CH₂Cl₂/EtOAc; gradient elution) to yield the target compound

(yield 15–43%).

[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]acetic acid methyl

ester (25): A white solid (294 mg, 86%); mp: 71–728C; ¹H NMR

(270 MHz, CDCl₃): d=1.65–1.85 (m, 6H), 1.90 (d, J=2.9 Hz, 6H),

2.06 (brs, 3H), 3.54 (s, 2H), 3.66 (s, 3H), 4.82 (s, 2H), 6.80 (dt, J=

8.7, 2.9 Hz, 2H), 7.16 (dt, J=8.7, 2.9 Hz, 2H); LC–MS (APCI) m/z:

341.7 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for C₂₁H₂₇O₄:

343.1904, found: 343.1892; HPLC: t_R=2.23 min (98%) in 10% H₂O/

CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)benzoic acid methyl

ester (32): A white solid (61 mg, 15%); mp: 87–908C; ¹H NMR

(270 MHz, CDCl₃): d=1.60–1.79 (m, 6H), 1.80 (d, J=2.7 Hz, 6H),

2.01 (brs, 3H), 3.90 (s, 3H), 4.32 (s, 2H), 4.61 (s, 2H), 7.42 (d, J=

8.2 Hz, 2H), 8.00 (d app, J=8.4 Hz, 2H); LC–MS (APCI) m/z: 365.5

[M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₁H₂₇O₄: 343.1904,

found: 343.1897; HPLC: t_R=2.20 min (97%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(biphenyl-4-yloxy)ethanone (26):

A white

1

solid (197 mg, 57%); mp: 117–118.58C; H NMR (270 MHz, CDCl₃):

d=1.70–1.81 (m, 6H), 1.94 (d, J=2.8 Hz, 6H), 2.08 (brs, 3H), 4.89

(s, 2H), 6.92 (dt, J=8.7, 3.2 Hz, 2H), 7.30 (dt, J=7.2, 1.3 Hz, 1H),

7.37–7.42 (m, 2H), 7.47–7.54 (m, 4H); LC–MS (APCI) m/z: 347

[M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₄H₂₇O₂: 347.2011,

found: 347.2002; HPLC: t_R=5.25 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(biphenyl-4-ylmethoxy)ethanone (33): White

1

crystals (81 mg, 43%); mp: 80–828C; H NMR (270 MHz, CDCl₃): d=

1-Adamantan-1-yl-2-(4-trifluoromethyl-phenoxy)ethanone (27):

A white solid (321 mg, 95%); mp: 78–808C; ¹H NMR (270 MHz,

CDCl₃): d=1.65–1.85 (m, 6H), 1.91 (d, J=3.0 Hz, 6H), 2.08 (brs,

3H), 4.90 (s, 2H), 6.88 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H);

LC–MS (APCI) m/z: 337.0 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd

for C₁₉H₂₂F₃O₂: 339.1566, found: 339.1565; HPLC: t_R=3.30 min

(97%) in 10% H₂O/CH₃CN.

1.79–1.61 (m, 6H), 1.82 (d app, J=3.0 Hz, 6H), 2.02 (brs, 3H), 4.34

(s, 2H), 4.62 (s, 2H), 7.29–7.37 (m, 1H), 7.39–7.47 (m, 4H), 7.54–7.62

(m, 4H); LC–MS (APCI) m/z: 383.58 [M+Na]⁺; HRMS (FAB) m/z

[M+NH₄]⁺calcd for C₂₄H₃₂NO₂: 378.2428, found: 378.2424; HPLC:

t_R=3.99 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-trifluoromethylbenzyloxy)ethanone (34):

A white solid (88 mg,32%); mp: 108–1118C; ¹H NMR (270 MHz,

CDCl₃): d=1.60–1.78 (m, 6H), 1.80 (d, J=2.5 Hz, 6H), 2.01 (brs,

3H), 4.34 (s, 2H), 4.60 (s, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.58 (d, J=

8.3 Hz, 2H); LC–MS (APCI) m/z: 375.2 [M+Na]⁺; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₀H₂₄F₃O₂: 353.1723, found: 353.1710; HPLC:

t_R=3.94 min (99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(3-trifluoromethyl-phenoxy)ethanone (28):

A white solid (337 mg, 99%); mp: 87–928C; ¹H NMR (270 MHz,

CDCl₃): d=1.65–1.88 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.07 (brs,

3H), 4.88 (s, 2H), 7.01 (brdd, J=8.3, 2.5 Hz, 1H), 7.05 (brs, 1H),

7.20 (brd, J=7.7 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H); LC–MS (APCI) m/z:

337 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for C₁₉H₂₂F₃O₂:

339.1566, found: 339.1560; HPLC: t_R=3.96 min (>99%) in 10%

H₂O/CH₃CN.

1-Adamantan-1-yl-2-(3-trifluoromethylbenzyloxy)ethanone (35):

A yellow solid (30 mg, 15%); mp: 45.5–508C; ¹H NMR (270 MHz,

CDCl₃): d=1.60–1.80 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.02 (brs,

3H), 4.36 (s, 2H), 4.60 (s, 2H), 7.43–7.59 (m, 3H), 7.62 (s, 1H); LC–

MS (APCI) m/z: 375.0 [M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₀H₂₄F₃O₂: 353.1723, found: 353.1716; HPLC: t_R=4.12 min (97%)

in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-phenoxy)ethanone (29): A white

crystalline solid (243 mg, 80%); mp: 112.5–113.58C; ¹H NMR

(300 MHz, CDCl₃): d=1.71–1.83 (m, 6H), 1.93 (d, J=2.7 Hz, 6H),

2.10 (brs, 3H), 4.84 (s, 2H), 6.80 (dt, J=8.9, 2.2 Hz, 2H), 7.23 (dt,

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1037

B. V. L. Potter et al.

MED

1-Adamantan-1-yl-2-(4-methylbenzyloxy)ethanone (36): White

crystals (33 mg, 28%); mp: 63–658C; H NMR (270 MHz, CDCl₃): d=

1.59–1.98 (m, 12H), 2.01 (brs, 3H), 2.33 (s, 3H), 4.27 (s, 2H), 4.53 (s,

2H), 7.11–7.19 (m, 2H), 7.25 (m, 2H); LC–MS (APCI) m/z: 299

[M+H]⁺; HRMS (FAB) m/z [M+NH₄]⁺calcd for C₂₀H₃₀NO₂: 316.2271,

found: 316.2270; HPLC: t_R=9.40 min (>99%) in 10% H₂O/CH₃CN.

night and then extracted twice with CH₂Cl₂. The organic phase was

washed with 5% aq NaHCO₃and brine, dried over MgSO₄and

then concentrated in vacuo. The crude mixture was purified by

flash chromatography with EtOAc/hexane or MeOH/CH₂Cl₂using

gradient elution to give the expected amide (yield 33–88%).

1

4-(2-Adamantan-1-yl-2-oxoethoxy)benzamide (42): A white solid

(33 mg, 33%); mp: 176–179.58C; ¹H NMR (270 MHz, CDCl₃): d=

1.60–1.82 (m, 6H), 1.91 (d, J=2.2 Hz, 6H), 2.08 (brs, 3H), 4.91 (s,

2H), 5.77 (brs, 1H), 5.99 (brs, 1H), 6.86 (d, J=8.5 Hz, 2H), 7.73 (d,

J=8.8 Hz, 2H); LC–MS (APCI) m/z: 312 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₄NO₃: 314.1751, found: 314.1749; HPLC: t_R=

2.00 min (98%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-methoxy-benzyloxy)ethanone (37): An

off-white oil (69 mg, 16%); H NMR (270 MHz, CDCl₃): d=1.60–1.88

1

(m, 12H), 1.92–2.18 (brs, 3H), 3.80 (s, 3H), 4.25 (s, 2H), 4.49 (s, 2H),

6.86 (d app, J=8.7 Hz, 2H), 7.27 (d app, J=8.4 Hz, 2H); LC–MS

(APCI) m/z: 337 [M+Na]⁺; HRMS (FAB) m/z [M+NH₄]⁺calcd for

C₂₀H₃₀NO₃: 332.2220 found 332.2222; HPLC: t_R=7.00 min (>99%)

in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-methylbenzamide (43):

A

white solid (39 mg, 37%); mp: 126.5–1288C; ¹H NMR (270 MHz,

CDCl₃): d=1.66–1.83 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.07 (brs,

3H), 2.96 (d, J=4.9 Hz, 3H), 4.88 (s, 2H), 6.08 (brs, 1H), 6.83 (d

app, J=8.9 Hz, 2H), 7.68 (d app, J=9.1 Hz, 2H); LC–MS (APCI) m/z:

351 [M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₆NO₃:

329.1747, found: 329.1755; HPLC: t_R=2.55 min (98%) in 10% H₂O/

CH₃CN.

1-Adamantan-1-yl-2-(3,4-dimethoxy-benzyloxy)ethanone (38): A

solution of 3,4-dimethoxybenzyl alcohol (0.139 mL, 0.97 mmol) and

1-adamantyl bromomethyl ketone (250 mg, 0.97 mmol) in toluene

(7 mL) was treated with tBuOK (217 mg, 1.94 mmol) at RT and was

stirred overnight. The reaction was quenched with water, extracted

twice with EtOAc, washed with brine, dried over MgSO₄and con-

centrated in vacuo. The crude mixture was purified using flash

chromatography using a gradient of 0–50% EtOAc in hexane to

give the target compound (47 mg, 14%) as white solid; mp 60.5–

63.58C; ¹H NMR (270 MHz, CDCl₃): d=1.60–1.78 (m, 6H), 1.78 (d,

J=2.7 Hz, 6H), 2.00 (brs, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 4.26 (s, 2H),

4.50 (s, 2H), 6.82 (s, 1H), 6.84 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz,

1H); LC–MS (APCI) m/z: 367 [M+Na]⁺; HRMS (FAB) m/z [M+Na]⁺

calcd for C₂₁H₂₈O₄Na: 367.1880, found: 367.1865; HPLC: t_R=

2.88 min (98%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-ethylbenzamide (44):

A

white solid (60 mg, 55%); mp: 141–142.58C; ¹H NMR (270 MHz,

CDCl₃): d=1.20 (t, J=7.4 Hz, 3H), 1.64–1.82 (m, 6H), 1.90 (d, J=

2.7 Hz, 6H), 2.07 (brs, 3H), 3.38–3.50 (m, 2H), 4.88 (s, 2H), 6.11

(brs, 1H), 6.83 (d app, J=8.9 Hz, 2H), 7.68 (d app, J=8.9 Hz, 2H);

LC–MS (APCI) m/z: 340 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₁H₂₈NO₃: 342.2064, found: 342.2063; HPLC: t_R=1.88 min (97%) in

10% H₂O/CH₃CN at 1.0 mLmin^ꢀ1

.

1-Adamantan-1-yl-2-(4-chloro-benzyloxy)ethanone (39): The title

compound was synthesised by method C as white solid (52 mg,

21%); mp: 91–928C; ¹H NMR (270 MHz, CDCl₃): d=1.58–1.72 (m,

6H), 1.75 (d, J=2.7 Hz, 6H), 2.00 (brs, 3H), 4.20 (s, 2H), 4.48 (s,

2H), 7.25 (s, 4H); LC–MS (APCI) m/z: 319 [M+H]⁺; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₄ClO₂: 319.1465, found: 319.1460; HPLC:

t_R=4.69 min (98%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-isopropylbenzamide (45): A

white solid (57. mg, 50%); mp: 161–1678C; ¹H NMR (270 MHz,

CDCl₃): d=1.21 (d, J=6.7 Hz, 6H), 1.64–1.85 (m, 6H), 1.90 (d, J=

2.7 Hz, 6H), 2.06 (brs, 3H), 4.16–4.30 (m, 1H), 4.87 (s, 2H), 5.87 (d,

J=7.4 Hz, 1H), 6.82 (d app, J=8.9 Hz, 2H), 7.65 (d app, J=8.9 Hz,

2H); LC–MS (APCI) m/z: 354 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺

calcd for C₂₂H₃₀NO₃: 356.2220, found: 356.2213; HPLC: t_R=1.95 min

(98%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)benzoic acid (40): The target

compound was prepared by hydrolysis of 23 (100 mg, 0.30 mmol)

in MeOH/H₂O (2.5–0.5 mL) with LiOH (38 mg, 1.6 mmol) at RT. A

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-tert-butylbenzamide (46): A

white solid (41 mg, 35%); mp: 179–1818C; ¹H NMR (270 MHz,

CDCl₃): d=1.41 (s, 9H), 1.65–1.82 (m, 6H), 1.90 (d, J=2.7 Hz, 6H),

2.07 (brs, 3H), 4.87 (s, 2H), 5.84 (brs, 1H), 6.83 (d app, J=8.9 Hz,

2H), 7.64 (d app, J=8.9 Hz, 2H); LC–MS (APCI) m/z: 368 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₃H₃₂NO₃: 370.2377, found:

370.2376; HPLC: t_R=2.29 min (98%) in 10% H₂O/CH₃CN.

1

white solid (75 mg, 79%) was obtained; mp: 184–1878C; H NMR

(270 MHz, CDCl₃): d=1.69–1.85 (m, 6H), 1.92 (d, J=2.7 Hz, 6H),

2.08 (brs, 3H), 4.93 (s, 2H), 6.87 (d, J=8.9 Hz, 2H), 8.03 (d, J=

8.9 Hz, 2H); LC–MS (APCI) m/z: 313 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₃O₄: 315.1591, found: 315.1600; HPLC: t_R=

1.28 min (98%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N,N-diethylbenzamide (47): A

white solid (44 mg, 37%); mp: 103–104.58C; ¹H NMR (270 MHz,

CDCl₃): d=1.15 (brs, 6H), 1.64–1.84 (m, 6H), 1.91 (d, J=2.7 Hz,

6H), 2.07 (brs, 3H), 3.37 (brs, 4H), 4.86 (s, 2H), 6.83 (d app, J=

8.9 Hz, 2H), 7.30 (d app, J=8.9 Hz, 2H); LC–MS (APCI) m/z: 392

[M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₃H₃₂NO₃: 370.2377,

found: 370.2370; HPLC: t_R=2.26 min (97%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)benzoic acid (41): The target

compound was prepared by hydrolysis of 24 (880 mg, 2.67 mmol)

in MeOH/H₂O (23–4 mL) with LiOH (337 mg, 8 mmol) at RT. A white

solid (797 mg, 99%) was obtained; mp: 153–158.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.67–1.85 (m, 6H), 1.93 (d, J=2.9 Hz, 6H),

2.09 (brs, 3H), 4.91 (s, 2H), 7.17 (ddd, J=8.4, 2.7, 1.0 Hz, 1H), 7.37

(t app, J=8.2 Hz, 1H), 7.51 (dd, J=2.7, 1.5 Hz, 1H), 7.72 (dt, J=7.9,

1.2 Hz, 1H); LC–MS (APCI) m/z: 313 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₃O₄: 315.1591, found: 315.1580; HPLC: t_R=

1.21 min (97%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-phenylbenzamide (48):

A

white solid (55 mg, 44%); mp: 183–1858C; ¹H NMR (270 MHz,

CDCl₃): d=1.65–1.90 (m, 6H), 1.93 (s app, 6H), 2.09 (brs, 3H), 4.93

(s, 2H), 6.91 (d app, J=8.9 Hz, 2H), 7.13 (t, J=7.2 Hz, 1H), 7.35 (t,

J=7.4 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.71 (brs, 1H), 7.80 (d app,

J=8.7 Hz, 2H); LC–MS (APCI) m/z: 388 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₅H₂₈NO₃: 390.2064, found: 390.2066; HPLC: t_R=

2.18 min (99%) in 10% H₂O/CH₃CN.

Method D: Synthesis of the carboxamide derivatives 42–58

A solution of the carboxylic acid (1.0 equiv) in CH₂Cl₂(5 mL) was

treated 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-

1038

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-benzylbenzamide (49):

A

LC–MS (APCI) m/z: 392 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₄H₂₈NO₄: 394.2013, found: 394.2006; HPLC: t_R=2.28 min (>99%)

in 10% H₂O/CH₃CN.

yellow solid (30 mg, 40%); mp: 143–1468C; ¹H NMR (270 MHz,

CDCl₃): d=1.85–1.62 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.03 (brs,

3H), 4.60 (d, J=5.7 Hz, 2H), 4.88 (s, 2H), 6.35 (t, J=5.2 Hz, 1H),

6.84 (d app, J=8.9 Hz, 2H), 7.24–7.34 (m, 5H), 7.72 (d app, J=

8.9 Hz, 2H); LC–MS (APCI) m/z: 402 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₆H₃₀NO₃: 404.2220, found: 404.2224; HPLC: t_R=

2.11 min (>99%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-benzylbenzamide (57):

A

white solid (77 mg, 60%); mp: 135.5–1398C; ¹H NMR (270 MHz,

CDCl₃): d=1.64–1.82 (m, 6H), 1.88 (d, J=2.7 Hz, 6H), 2.05 (brs,

3H), 4.59 (d, J=5.7 Hz, 2H), 4.87 (s, 2H), 6.57 (brt, J=5.2 Hz, 1H),

7.01 (dt, J=7.0, 2.5 Hz, 1H), 7.22–7.34 (m, 8H); LC–MS (APCI) m/z:

402 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for C₂₆H₃₀NO₃:

404.2220, found: 404.2215; HPLC: t_R=2.43 min (98%) in 10% H₂O/

CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxy)-N-furan-2-ylmethylbenza-

mide (50): A white solid (70 mg, 56%); mp: 158–1608C; ¹H NMR

(270 MHz, CDCl₃): d=1.63–1.83 (m, 6H), 1.90 (d, J=2.7 Hz, 6H),

2.06 (brs, 3H), 4.58 (d, J=5.5 Hz, 2H), 4.87 (s, 2H), 6.27 (ddd, J=

15.0, 3.0, 2.0 Hz, 1H), 6.44 (t, J=4.9 Hz, 1H), 6.83 (d app, J=8.9 Hz,

2H), 7.34 (dd, J=2.0, 1.0 Hz, 1H), 7.71 (d app, J=8.9 Hz, 2H); LC–

MS (APCI) m/z: 392 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₄H₂₈NO₄: 394.2013, found: 394.2016; HPLC: t_R=1.89 min (96%) in

10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-phenylbenzamide (58): Col-

1

ourless crystals (89 mg, 71%); mp: 148–1518C; H NMR (270 MHz,

CDCl₃): d=1.64–1.82 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.06 (brs,

3H), 4.87 (s, 2H), 7.00 (ddd, J=8.0, 2.7, 1.2 Hz, 1H), 7.13 (tt, J=7.4,

1.2 Hz, 1H), 7.26–7.40 (m, 5H), 7.63 (dt, J=9.0 Hz, 2H), 8.12 (brs,

1H); LC–MS (APCI) m/z: 388 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺

calcd for C₂₅H₂₈NO₃: 390.2064, found: 390.2058; HPLC: t_R=3.10 min

(99%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)benzamide (51): A white solid

(24 mg, 18%); mp: 180.5–1888C; ¹H NMR (270 MHz, CDCl₃): d=

1.61–1.84 (m, 6H), 1.90 (d, J=3.0 Hz, 6H), 2.06 (brs, 3H), 4.90 (s,

2H), 5.81 (brs, 1H), 6.18 (brs, 1H), 6.98–7.11 (m, 1H), 7.24–7.33 (m,

3H); LC–MS (APCI) m/z: 312 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺

calcd for C₁₉H₂₄NO₃: 314.1751, found: 314.1758; HPLC: t_R=2.05 min

(98%) in 10% H₂O/CH₃CN.

[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]acetic acid (59): Hy-

drolysis of 25 (965 mg, 2.82 mmol) in MeOH/H₂O (24–4 mL) with

LiOH (355 mg, 8.45 mmol) at RT gave the target compound as a

1

white solid (886 mg, 96%); mp: 152.2–153.68C; H NMR (270 MHz,

CDCl₃): d=1.65–1.82 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.07 (brs,

3H), 3.56 (s, 2H), 4.82 (s, 2H), 6.81 (d, J=8.9 Hz, 2H), 7.17 (d, J=

8.9 Hz, 2H); LC–MS (APCI) m/z: 327 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₀H₂₅O₄: 329.1747, found: 329.1748; HPLC: t_R=

1.23 min (97%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-methylbenzamide (52):

A

white solid(63 mg, 61%); mp: 183.5–185.58C; ¹H NMR (270 MHz,

CDCl₃): d=1.82–1.64 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.06 (brs,

3H), 2.96 (d, J=4.9 Hz, 3H), 4.88 (s, 2H), 6.32 (brs, 1H), 6.95–7.03

(m, 1H), 7.22–7.31 (m, 3H); LC–MS (APCI) m/z: 326 [MꢀH]^ꢀ; HRMS

(FAB) m/z [M+H]⁺calcd for C₂₀H₂₆NO₃: 328.1907, found: 328.1893;

HPLC: t_R=2.12 min (97%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)benzoic acid (60): Hy-

drolysis of 32 (294 mg, 0.86 mmol) in THF/H₂O (8–1 mL) with LiOH

(105 mg, 2.57 mmol) at RT gave the target compound as a white

1

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-ethylbenzamide (53): Col-

solid (162 mg, 57%); mp: >2608C (dec.); H NMR (270 MHz, CDCl₃):

1

ourless crystals (57 mg, 52%); mp: 107–1108C; H NMR (270 MHz,

d=1.61–1.79 (m, 6H), 1.81 (d, J=2.7 Hz, 6H), 2.02 (brs, 3H), 4.35

(s, 2H), 4.64 (s, 2H), 7.46 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H);

LC–MS (APCI) m/z: 327 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₀H₂₅O₄[M+H]⁺329.1747, found: 329.1751; HPLC: t_R=1.67 min

(97%) in 10% H₂O/CH₃CN.

CDCl₃): d=1.21 (t, J=7.2 Hz, 3H), 1.63–1.82 (m, 6H), 1.89 (d, J=

2.7 Hz, 6H), 2.05 (brs, 3H), 3.38–3.50 (m, 2H), 4.87 (s, 2H), 6.27

(brs, 1H), 6.94–7.03 (m, 1H), 7.22–7.29 (m, 3H); LC–MS (APCI) m/z:

340 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for C₂₁H₂₈NO₃:

342.2064, found: 342.2051; HPLC: t_R=2.50 min (98%) in 10% H₂O/

CH₃CN.

Method D: Synthesis of carboxamide derivatives 61–73

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-isopropylbenzamide (54):

Colourless crystals (70 mg, 61%); mp: 158–1618C; ¹H NMR

(270 MHz, CDCl₃): d=1.21 (d, J=6.4 Hz, 6H), 1.63–1.81 (m, 6H),

1.88 (d, J=2.7 Hz, 6H), 2.05 (brs, 3H), 4.15–4.30 (m, 1H), 4.87 (s,

2H), 6.03 (d, J=7.4 Hz, 1H), 6.93–7.02 (m, 1H), 7.22–7.29 (m, 3H);

LC–MS (APCI) m/z: 354 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₂H₃₀NO₃: 356.2220, found: 356.2213; HPLC: t_R=2.66 min (98%) in

10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-methyl-acet-

1

amide (61): A cream solid (41 mg, 40%); mp: 161–1628C; H NMR

(270 MHz, CDCl₃): d=1.65–1.83 (m, 6H), 1.90 (d, J=2.7 Hz, 6H),

2.07 (brs, 3H), 2.72 (d, J=4.7 Hz, 3H), 3.48 (s, 2H), 4.85 (s, 2H),5.39

(brs, 1H), 6.81 (d app, J=8.6 Hz, 2H), 7.12 (d app, J=8.9 Hz, 2H);

LC–MS (APCI) m/z: 340 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₁H₂₈NO₃: 342.2064, found: 342.2052; HPLC: t_R=2.21 min (97%) in

10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-tert-butylbenzamide (55): A

white solid (67 mg, 57%); mp: 139.5–1418C; ¹H NMR (270 MHz,

CDCl₃): d=1.43 (s, 9H), 1.66–1.80 (m, 6H), 1.89 (d, J=2.7 Hz, 6H),

2.06 (brs, 3H), 4.87 (s, 2H), 5.96 (brs, 1H), 6.90 (ddd, J=7.7, 2.9,

1.7 Hz, 1H), 7.19–7.30 (m, 3H); LC–MS (APCI) m/z: 368 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₃H₃₂NO₃: 370.2377, found:

370.2364; HPLC: t_R=2.82 min (>99%) in 10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N,N-dimethyl-acet-

1

amide (62): A yellow oil (54 mg, 51%); H NMR (270 MHz, CDCl₃):

d=1.65–1.82 (m, 6H), 1.88 (d, J=2.7 Hz, 6H), 2.09 (brs, 3H), 2.92

(s, 3H), 2.96 (s, 3H), 3.61 (s, 2H), 4.81 (s, 2H), 6.73–6.82 (m, 2H),

7.08–7.16 (m, 2H); LC–MS (APCI) m/z: 354 [MꢀH]^ꢀ; HRMS (FAB)

m/z [M+H]⁺calcd for C₂₂H₃₀NO₃: 356.2220, found: 356.2230; HPLC:

t_R=2.38 min (99%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethoxy)-N-furan-2-ylmethylbenza-

mide (56): A white solid (110 mg, 88%); mp: 120.5–123.58C;

¹H NMR (270 MHz, CDCl₃): d=1.61–1.80 (m, 6H), 1.86 (d, J=2.7 Hz,

6H), 2.03 (brs, 3H), 4.55 (d, J=5.6 Hz, 2H), 4.84 (s, 2H), 6.22 (dd,

J=3.2, 1.0 Hz, 1H), 6.28 (dd, J=3.2, 1.8 Hz, 1H), 6.77 (brt, J=

5.0 Hz, 1H), 6.97 (ddd, J=7.9, 2.7, 1.2 Hz, 1H), 7.19–7.37 (m, 4H);

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]acetamide (63):

A

cream solid (61 mg, 31%); mp: 101–1068C; ¹H NMR (270 MHz,

CDCl₃): d=1.60–1.85 (m, 6H), 1.90 (d, J=2.7 Hz, 6H), 2.06 (brs,

3H), 3.48 (s, 2H), 4.84 (s, 2H), 5.46 (brs, 1H), 5.62 (brs, 1H), 6.70–

6.86 (m, 2H), 7.08–7.20 (m, 2H); LC–MS (APCI) m/z: 326 [MꢀH]^ꢀ;

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1039

B. V. L. Potter et al.

MED

HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₆NO₃: 328.1907, found:

328.1912; HPLC: t_R=1.92 min (>99%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)-N-methylbenzamide

(71): A cream solid (43 mg, 60%); mp: 133.5–1398C; ¹H NMR

(270 MHz, CDCl₃): d=1.60–1.78 (m, 6H), 1.79 (d, J=2.7 Hz, 6H),

2.01 (brs, 3H), 2.98 (d, J=5.0 Hz, 3H), 4.31 (s, 2H), 4.58 (s, 2H),

6.29 (brd, J=3.7 Hz, NH), 7.39 (d app, J=8.4 Hz, 2H), 7.72 (d app,

J=8.4 Hz, 2H); LC–MS (APCI) m/z: 340 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₁H₂₈NO₃: 342.2064, found: 342.2051; HPLC: t_R=

2.11 min (97%) in 10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-ethyl-acetamide

(64): A cream solid (55 mg, 52%); mp: 141.5–146.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.03 (t, J=7.2 Hz, 3H), 1.64–1.82 (m, 6H),

1.90 (d, J=2.7 Hz, 6H), 2.06 (brs, 3H), 3.27 (m, 2H), 3.46 (s, 2H),

4.84 (s, 2H), 5.40 (brs, 1H), 6.81 (d app, J=8.7 Hz, 2H), 7.12 (d app,

J=8.9 Hz, 2H); LC–MS (APCI) m/z: 354 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₂H₃₀NO₃: 356.2220, found: 356.2220; HPLC: t_R=

2.06 min (96%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)-N,N-dimethylbenza-

mide (72): A white solid (57 mg, 54%); mp: 76–808C; ¹H NMR

(270 MHz, CDCl₃): d=1.58–1.80 (m, 6H), 1.80 (d, J=2.7 Hz, 6H),

2.00 (brs, 3H), 2.96 (brs, 3H), 3.09 (brs, 3H), 4.31 (s, 2H), 4.58 (s,

2H), 7.39 (s, 4H); LC–MS (APCI) m/z: 354 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₂H₃₀NO₃: 356.2220, found: 356.2210; HPLC: t_R=

2.35 min (98%) in 10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-isopropyl-acet-

1

amide (65): A cream solid (51 mg, 46%); mp: 132–1358C; H NMR

(270 MHz, CDCl₃): d=1.03 (d, J=6.4 Hz, 6H), 1.65–1.83 (m, 6H),

1.90 (d, J=2.7 Hz, 6H), 2.06 (brs, 3H), 3.44 (s, 2H), 3.93–4.15 (m,

1H), 4.84 (s, 2H), 5.18 (brd, J=5.9 Hz, 1H), 6.82 (d app, J=8.9 Hz,

2H), 7.13 (d app, J=8.7 Hz, 2H); LC–MS (APCI) m/z: 368 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₃H₃₂NO₃: 370.2877, found:

370.2366; HPLC: t_R=2.22 min (97%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)-N-benzylbenzamide

(73): An off-white solid (55 mg, 55%); mp: 126–1318C; ¹H NMR

(270 MHz, CDCl₃): d=1.58–1.75 (m, 6H), 1.79 (d, J=2.9 Hz, 6H),

2.02 (brs, 3H), 4.30 (s, 2H), 4.58 (s, 2H), 4.62 (d, J=5.7 Hz, 2H),

6.51 (brt, J=5.3 Hz, NH), 7.23–7.36 (m, 5H), 7.39 (d app, J=8.0 Hz,

2H), 7.76 (d app, J=8.0 Hz, 2H); LC–MS (APCI) m/z: 416 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₇H₃₂NO₃: 418.2377, found:

418.2373; HPLC: t_R=2.65 min (99%) in 10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-tert-butyl-acet-

1

amide (66): A white solid (83 mg, 48%); mp: 144–145.58C; H NMR

(270 MHz, CDCl₃): d=1.24 (s, 9H), 1.64–1.89 (m, 6H), 1.89 (d app,

J=2.7 Hz, 6H), 2.05 (brs, 3H), 3.38 (s, 2H), 4.82 (s, 2H), 5.21 (brs,

1H), 6.80 (d app, J=8.6 Hz, 2H), 7.10 (d app, J=8.6 Hz, 2H); LC–

MS (APCI) m/z: 382 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₄H₃₄NO₃: 384.2533, found: 384.2520; HPLC: t_R=2.14 min (98%) in

10% H₂O/CH₃CN.

Method E: Synthesis of adamantyl ethanone thioether deriv-

atives 74–82

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-benzyl-acet-

amide (67): A cream solid (89 mg, 71%); mp: 130.5–132.58C;

¹H NMR (270 MHz, CDCl₃): d=1.64–1.82 (m, 6H), 1.89 (d, J=2.7 Hz,

6H), 2.06 (brs, 3H), 3.51 (s, 2H), 4.36 (d, J=6.0 Hz, 2H), 4.81 (s,

2H), 5.88 (brs, 1H), 5.90 (d app, J=8.7 Hz, 2H), 7.10–7.78 (m, 4H),

7.20–7.31 (m, 3H); LC–MS (APCI) m/z: 416 [MꢀH]^ꢀ; HRMS (FAB)

m/z [M+H]⁺calcd for C₂₇H₃₂NO₃: 418.2377, found: 418.2368; HPLC:

t_R=2.07 min (99%) in 10% H₂O/CH₃CN.

A solution of 1-adamantyl bromomethyl ketone (1 equiv) in CH₃CN

(15 mL) was treated with the corresponding thiophenol or thioal-

cohol (1.1 equiv), followed by Et₃N (3 equiv). The mixture was

stirred at RT overnight. 2-Chloro-tritylchloride resin (1.1 equiv,

1.6 mmolg^ꢀ1) was added and the mixture was stirred for 2 h, fil-

tered and concentrated in vacuo to give the crude product. Purifi-

cation using flash chromatography yielded the title compound

(yield 27–99%).

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-phenyl-acet-

amide (68): A cream solid (56 mg, 46%); mp: 152.5–154.58C;

¹H NMR (270 MHz, CDCl₃): d=1.66–1.84 (m, 6H), 1.91 (d, J=2.9 Hz,

6H), 2.07 (brs, 3H), 3.64 (s, 2H), 4.86 (s, 2H), 6.52 (d app, J=8.7 Hz,

2H), 7.60 (tt, J=7.2, 1.2 Hz, 1H), 7.15–7.30 (m, 4H), 7.37–7.43 (m,

2H); LC–MS (APCI) m/z: 402 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺

calcd for C₂₆H₃₀NO₃: 404.2220, found: 404.2206; HPLC: t_R=2.21 min

(98%) in 10% H₂O/CH₃CN.

N-[3-(2-Adamantan-1-yl-2-oxoethylsulfanyl)phenyl]acetamide

(74): Purification using flash chromatography (EtOAc/CH₂Cl₂; gradi-

ent elution) gave the title product (300 mg, 44%) as a white solid;

1

mp: 122–123.58C; H NMR (270 MHz, CDCl₃): d=1.64–1.78 (m, 6H),

1.85 (d, J=2.7 Hz, 6H), 2.03 (brs, 3H), 2.13 (s, 3H), 3.93 (s, 2H),

7.04 (d, J=8.2 Hz, 1H), 7.18 (t, J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz,

1H), 7.45 (brs, 1H), 7.53 (brs, 1H); LC–MS (ESI) m/z: 342 [MꢀH]^ꢀ;

HRMS (ESI) m/z [M+Na]⁺calcd for C₂₀H₂₅NO₂SNa: 366.1504, found:

366.1470; HPLC: t_R=2.27 min (99%) in 10% H₂O/CH₃CN.

2-[4-(2-Adamantan-1-yl-2-oxoethoxy)phenyl]-N-furan-2-ylmeth-

yl-acetamide (69): A yellow semisolid (35 mg, 28%); ¹H NMR

(270 MHz, CDCl₃): d=1.65–1.83 (m, 6H), 1.90 (d, J=2.7 Hz, 6H),

2.07 (brs, 3H), 3.50 (s, 2H), 4.36 (d, J=5.7 Hz, 2H), 4.84 (s, 2H),

5.74 (brs, 1H), 6.10–6.13 (m, 1H), 6.26 (dd, J=3.2, 1.7 Hz, 1H), 6.81

(d app, J=8.9 Hz, 2H), 7.13 (d app, J=8.9 Hz, 2H), 7.29 (dd, J=2.0,

1.0 Hz, 1H); LC–MS (APCI) m/z: 406 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+H]⁺calcd for C₂₅H₃₀NO₄: 408.2169, found: 408.2174; HPLC: t_R=

2.17 min (96%) in 10% H₂O/CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethylsulfanyl)phenyl]acetamide

(75): Purification using flash chromatography (EtOAc/CH₂Cl₂; gradi-

ent elution) yielded the title compound as a white solid (520 mg,

1

78%); mp: 110–1118C; H NMR (270 MHz, CDCl₃): d=1.62–1.75 (m,

6H), 1.82 (d, J=2.8 Hz, 6H), 2.03 (brs, 3H), 2.16 (s, 3H), 3.86 (s,

2H), 7.21 (brs, 1H), 7.34 (dd, J=7.0, 2.0 Hz, 2H), 7.42 (dd, J=7.0,

2.0 Hz, 2H); LC–MS (APCI) m/z: 342 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+Na]⁺calcd for C₂₀H₂₅NO₂SNa: 366.1504, found: 366.1476;

HPLC: t_R=5.25 min (>99%) in 10% H₂O/CH₃CN.

4-(2-Adamantan-1-yl-2-oxoethoxymethyl)benzamide (70):

A

white solid (20 mg, 25%); mp: 143–1498C; ¹H NMR (270 MHz,

CDCl₃): d=1.59–1.83 (m, 6H), 1.85 (d, J=2.7 Hz, 6H), 2.02 (brs,

3H), 4.32 (s, 2H), 4.61 (s, 2H), 5.58 (brs, 1H), 6.05 (brs, 1H), 7.44 (d,

J=5.9 Hz, 2H), 7.70–7.82 (m, 2H); LC–MS (APCI) m/z: 326 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₆NO₃: 328.1907, found:

328.1913; HPLC: t_R=3.18 min (>99%) in 30% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-phenylsulfanyl)ethanone (76): Pu-

rification using flash chromatography (hexane/CH₂Cl₂; gradient elu-

tion) yielded the title compound as a white crystalline solid

(98 mg, 61%); mp: 90–918C; ¹H NMR (270 MHz, CDCl₃): d=1.64–

1.76 (m, 6H), 1.83 (d, J=2.8 Hz, 6H), 2.04 (brs, 3H), 3.88 (s, 2H),

7.20–7.26 (m, 4H); LC–MS (APCI) m/z: 319 [MꢀH]^ꢀ; HRMS (FAB)

1040

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

m/z [M+Na]⁺calcd for C₁₈H₂₁ClOSNa: 343.0899, found: 343.0895;

HPLC: t_R=4.23 min (>98%) in 20% H₂O/CH₃CN.

3H), 3.78 (d, J=16 Hz, 1H), 4.13 (d, J=16 Hz, 1H), 7.20 (d, J=

8.0 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.89 (s, 1H), 8.14 (d, J=8.0 Hz,

1H), 8.68 (s, 1H); LC–MS (ESI) m/z: 358 [MꢀH]^ꢀ; HRMS (ESI) m/z

[M+Na]⁺calcd for C₂₀H₂₅NNaO₃S: 382.1453, found: 382.1426;

HPLC: t_R=1.71 min (>99%) in 10% H₂O/CH₃CN. Compound 91

was obtained as a white solid (21 mg, 7%); mp: 167–1688C;

¹H NMR (270 MHz, CDCl₃): d=1.60–1.75 (m, 12H), 2.03 (brs, 3H),

2.20 (s, 3H), 4.32 (s, 2H), 7.51 (t, J=8.1 Hz, 1H), 7.64 (d, J=8.3 Hz,

2H), 7.88 (s, 1H), 8.12 (d, J=8.2 Hz, 1H); LC–MS (ESI) m/z: 374

[MꢀH]^ꢀ; HRMS (ESI) m/z [M+Na]⁺calcd for C₂₀H₂₅NNaO₄S:

398.1402, found: 398.1383; HPLC: t_R=1.74 min (98%) in 10% H₂O/

CH₃CN.

1-Adamantan-1-yl-2-p-tolylsulfanyl-ethanone (77): Purification

using flash chromatography (hexane/CH₂Cl₂; gradient elution)

yielded the title compound as a white crystalline solid (107 mg,

1

71%); mp: 65–67.58C; H NMR (270 MHz, CDCl₃): d=1.62 (m, 6H),

1.77 (d, J=3.0 Hz, 6H), 1.97 (brs, 3H), 2.23 (s, 3H), 3.80 (s, 2H),

7.02 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H); LC–MS (APCI) m/z:

299 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+Na]⁺calcd for C₁₉H₂₄OSNa:

323.1446, found: 323.1422; HPLC: t_R=4.44 min (>99%) in 20%

H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-benzylsulfanyl)ethanone (78): Pu-

rification using flash chromatography (hexane/EtOAc; gradient elu-

tion) yielded the title compound as a white crystalline solid

Method F: Synthesis of the adamantyl ethanone sulfoxide

derivatives 84–90

1

(330 mg, 99%); mp: 73–758C; H NMR (300 MHz, CDCl₃): d=1.66–

1.78 (m, 6H), 1.83 (d, J=2.8 Hz, 6H), 2.06 (brs, 3H), 3.20 (s, 2H),

3.70 (s, 2H), 7.26 (s, 4H); LC–MS (APCI) m/z: 333 [MꢀH]^ꢀ; HRMS

(FAB) m/z [M+Na]⁺calcd for C₁₉H₂₃ClOSNa: 357.1056, found:

357.1035; HPLC: t_R=3.55 min (>98%) in 4% H₂O/CH₃CN.

A cold solution of the corresponding thioether derivative (1 equiv)

in CH₂Cl₂(10 mL) was treated with m-CPBA (1.2 equiv). The mixture

was stirred at ꢀ108C for 20 min, partitioned between CH₂Cl₂and

5% aq Na₂CO₃. The organic phase was washed with brine, dried

over MgSO₄and concentrated in vacuo to give crude product. Pu-

rification using flash chromatography (EtOAc/CH₂Cl₂; gradient elu-

tion) yielded the title compound (20–80%).

1-Adamantan-1-yl-2-(2-chloro-benzylsulfanyl)ethanone (79): Pu-

rification using flash chromatography (hexane/EtOAc; gradient elu-

tion) yielded the title compound as a white solid (123 mg, 95%);

mp: 43–478C; ¹H NMR (270 MHz, CDCl₃): d=1.60–1.80 (m, 6H),

7.57–7.52 (m, 1H), 1.83 (d, J=2.7 Hz, 6H), 2.03 (brs, 3H), 3.29 (s,

2H), 3.83 (s, 2H), 7.14–7.23 (m, 2H), 7.32–7.39 (m, 2H); LC–MS (ESI)

m/z: 357 [M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₁₉H₂₄ClOS:

335.1231, found: 335.1225;HPLC: t_R=5.88 min (98%) in 10% H₂O/

CH₃CN.

N-[4-(2-Adamantan-1-yl-2-oxoethanesulfinyl)phenyl]acetamide

(84): Purification using flash chromatography (EtOAc/CH₂Cl₂; gradi-

ent elution) yielded the title compound as a white solid (200 mg,

1

76%); mp: 173.5–175.58C; H NMR (270 MHz, CDCl₃): d=1.59–1.73

(m, 12H), 2.01 (brs, 3H), 2.19 (s, 3H), 3.78 (d, J=5.6 Hz, 1H), 4.15

(d, J=5.6 Hz, 1H), 7.65 (m, 5H); LC–MS (APCI) m/z: 358 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₂₀H₂₆NO₃S: 360.1633, found:

360.1621; HPLC: t_R=4.35 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(3-methylbenzylsulfanyl)ethanone (80): Pu-

rification using flash chromatography (hexane/EtOAc; gradient elu-

tion) gave the title compound as a transparent oil (110 mg, 27%);

¹H NMR (270 MHz, CDCl₃): d=1.62–1.78 (m, 6H), 1.81 (d, J=2.9 Hz,

6H), 2.02 (brs, 3H), 2.32 (s, 3H), 3.22 (s, 2H), 3.68 (s, 2H), 7.03–7.21

(m, 4H); LC–MS (APCI) m/z: 337 [M+Na]⁺; HRMS (FAB) m/z [M+H]⁺

calcd for C₂₀H₂₇OS: 315.1777, found: 315.1790; HPLC: t_R=9.56 min

(97%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-benzenesulfinyl)ethanone (85): A

white solid (46 mg, 44%); mp: 144–146.58C; ¹H NMR (270 MHz,

CDCl₃): d=1.55–1.78 (m, 12H), 2.01 (brs, 3H), 3.80 (d, J=15.3 Hz,

1H), 4.15 (d, J=15.3 Hz, 1H), 7.49 (dt, J=8.9, 2.2 Hz, 2H), 7.64 (dt,

J=8.6, 2.5 Hz, 2H); LC–MS (APCI) m/z: 335 [MꢀH]^ꢀ; HRMS (FAB)

m/z [M+H]⁺calcd for C₁₈H₂₂ClO₂S: 337.1024, found: 337.1018;

HPLC: t_R=5.74 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-tert-butylbenzylsulfanyl)ethanone (81): A

white solid (132 mg, 95%); mp: 64.5–688C; ¹H NMR (270 MHz,

CDCl₃): d=1.29 (s, 9H), 1.54–1.79 (m, 6H), 1.80 (m, 6H), 2.01 (brs,

3H), 3.17 (s, 2H), 3.68 (s, 2H), 7.22–7.34 (m, 4H); LC–MS (APCI)

m/z: 357 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₂₃H₃₃OS:

357.2247, found: 357.2248; HPLC: t_R=14.9 min (100%) in 10%

H₂O/CH₃CN.

1-Adamantan-1-yl-2-(toluene-4-sulfinyl)ethanone (86): A white

solid (70 mg, 67%); mp: 116.5–1188C; ¹H NMR (270 MHz, CDCl₃):

d=1.57–1.74 (m, 12H), 1.99 (brs, 3H), 2.39 (s, 3H), 3.75 (d, J=

15.1 Hz, 1H), 4.13 (d, J=15.3 Hz, 1H), 7.30 (d app, J=7.9 Hz, 2H),

7.56 (d app, J=8.1 Hz, 2H); LC–MS (APCI) m/z: 315 [MꢀH]^ꢀ; HRMS

(FAB) m/z [M+H]⁺calcd for C₁₉H₂₅O₂S: 317.1570, found: 317.1558;

HPLC: t_R=5.42 min (99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(2,4-dichloro-benzylsulfanyl)ethanone (82):

A clear semisolid (127 mg, 88%); ¹H NMR (270 MHz, CDCl₃): d=

1.62–1.78 (m, 6H) 1.83 (d, J=3.0 Hz, 6H), 2.03 (brs, 3H), 3.26 (s,

2H), 3.79 (s, 2H), 7.19 (dd, J=8.0, 2.0 Hz, 1H), 7.33 (d, J=8.0 Hz,

1H), 7.38 (d, J=2.0 Hz, 1H); LC–MS (APCI) m/z: 369 [M+H]⁺; HRMS

(FAB) m/z [M+H]⁺calcd for C₁₉H₂₃Cl₂OS: 369.0841 found 369.0847;

HPLC: t_R=12.93 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-phenylmethanesulfinyl)ethanone

(87): Purification using flash chromatography (EtOAc/CH₂Cl₂; gradi-

ent elution) yielded the title compound as a white crystalline solid

1

(95 mg, 46%); mp: 164–1668C; H NMR (300 MHz, CDCl₃): d=1.65–

1.75 (m, 6H), 1.86 (brs, 6H), 2.10 (brs, 3H), 3.57 (d, J=15.6 Hz, 1H),

3.90 (d, J=15.7 Hz, 1H), 4.00 (d, J=13.2 Hz, 1H), 4.11 (d, J=

13.2 Hz, 1H), 7.25 (dt, J=8.3, 2.0 Hz, 2H), 7.37 (dt, J=8.2, 2.0 Hz,

2H); LC–MS (APCI) m/z: 351 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺

calcd for C₁₉H₂₄ClO₂S: 351.1186, found: 351.1181; HPLC: t_R=

3.09 min (>99%) in 10% H₂O/CH₃CN.

N-[3-(2-Adamantan-1-yl-2-oxoethanesulfinyl)phenyl]acetamide

(83) and N-[3-(2-adamantan-1-yl-2-oxoethanesulfonyl)phenyl]a-

cetamide (91): A cold solution of 74 (270 mg, 0.79 mmol) in CH₂Cl₂

(30 mL) was treated with m-CPBA (215 mg, 60–77% purity). The

mixture was stirred at ꢀ108C for 45 min, partitioned between

CH₂Cl₂and 5% aq Na₂CO₃. The organic phase was washed with

brine, dried over MgSO₄and concentrated in vacuo. Purification

using flash chromatography (EtOAc/CH₂Cl₂; gradient elution) yield-

ed 83 as a white solid (177 mg, 62%); mp: 73–768C; ¹H NMR

(270 MHz, CDCl₃): d=1.59–1.73 (m, 12H), 2.00 (brs, 3H), 2.21 (s,

1-Adamantan-1-yl-2-(2-chloro-phenylmethanesulfinyl)ethanone

(88): The title compound was prepared as a white solid (190 mg,

80%); mp: 105.5–1088C; ¹H NMR (270 MHz, CDCl₃): d=1.57–1.85

(m, 12H), 2.03 (brs, 3H), 3.75 (d, J=15.5 Hz, 1H), 3.92 (d, J=

15.5 Hz, 1H), 4.15 (d, J=13.0 Hz, 1H), 4.42 (d, J=13.0 Hz, 1H),

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1041

B. V. L. Potter et al.

MED

7.22–7.30 (m, 2H), 7.36–7.44 (m, 2H); LC–MS (ESI) m/z 373

[M+Na]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₁₉H₂₄ClO₂S: 351.1186,

found: 351.1176; HPLC: t_R=2.54 min (99%) in 10% H₂O/CH₃CN.

(270 MHz, CDCl₃): d=1.58–1.68 (m, 6H), 1.73 (d, J=2.8 Hz, 6H),

2.02 (brs, 3H), 3.80 (s, 2H), 4.40 (s, 2H), 7.30 (dt, J=8.2, 2.0 Hz,

2H), 7.36 (dt, J=8.2, 2.0 Hz, 2H); LC–MS (APCI) m/z: 367 [M+H]⁺;

HRMS (FAB) m/z [M+NH₄]⁺calcd for C₁₉H₂₇ClNO₃S: 384.1400,

found: 384.1399; HPLC: t_R=3.14 min (98%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-tert-butyl-phenylmethanesulfinyl)etha-

1

none (89): A white solid (21 mg, 20%); mp: 144.5–1468C; H NMR

(270 MHz, CDCl₃): d=1.27 (s, 9H), 1.61–1.79 (m, 12H), 2.03 (m, 3H),

3.58 (d, J=15.6 Hz, 1H), 3.86 (d, J=15.6 Hz, 1H), 4.05 (d, J=

13.0 Hz, 1H), 4.20 (d, J=13.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.37

(d, J=8.2 Hz, 2H); LC–MS (APCI) m/z: 373 [M+H]⁺; HRMS (FAB)

m/z [M+H]⁺calcd for C₂₃H₃₃O₂S: 373.2196, found: 373.2194; HPLC:

t_R=7.13 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(2-chloro-phenylmethanesulfonyl)ethanone

(96): A white solid (270 mg, 94%); mp: 114–116.58C; ¹H NMR

(270 MHz, CDCl₃): d=1.60–1.82 (m, 6H), 1.82 (d, J=2.7 Hz, 6H),

2.08 (brs, 3H), 4.08 (s, 2H), 4.77 (s, 2H), 7.26–7.36 (m, 2H), 7.42–

7.47 (m, 1H), 7.52–7.57 (m, 1H); LC–MS (ESI): m/z: 365 [MꢀH]^ꢀ;

HRMS (FAB) m/z [M+H]⁺calcd for C₁₉H₂₄ClO₃S: 367.1129, found:

367.1125; HPLC: t_R=2.72 min (97%) 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(2,4-dichloro-benzylsulfanyl)ethanone (90):

A white solid (56 mg, 56%); mp: 126–1288C; ¹H NMR (270 MHz,

CDCl₃): d=1.64–1.85 (m, 12H), 2.07 (m, 3H), 3.78 (d, J=15.6 Hz,

1H), 3.95 (d, J=15.6 Hz, 1H), 4.12 (d, J=13.1 Hz, 1H), 4.42 (d, J=

12.9 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.46

(d, J=2.0 Hz, 1H); LC–MS (APCI) m/z: 385 (M+1)⁺; HRMS (FAB) m/z

[M+H]⁺calcd for C₁₉H₂₃Cl₂O₂S: 385.0790, found: 385.0788; HPLC:

t_R=6.19 min (>99%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2m-tolylmethanesulfonyl-ethanone (97):

A

white solid (277 mg, 81%); mp: 133–133.58C; ¹H NMR (270 MHz,

CDCl₃): d=1.60–1.75 (m, 6H), 1.77 (d, J=2.7 Hz, 6H), 2.06 (brs,

3H), 2.34 (s, 3H), 3.88 (s, 2H), 4.47 (s, 2H), 7.13–7.31 (m, 4H); LC–

MS (APCI) m/z: 345 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺calcd for

C₂₀H₂₇O₃S: 347.1675, found: 347.1667; HPLC: t_R=2.21 min (98%) in

10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-tert-butyl-phenylmethanesulfonyl)etha-

1

none (98): A white solid (262 mg, 57%); mp: 173–174.58C; H NMR

Method G: Synthesis of adamantyl ethanone sulfone deriva-

tives 92–99

(270 MHz, CDCl₃): d=1.30 (s, 9H), 1.60–1.75 (m, 6H), 1.77 (d, J=

2.9 Hz, 6H), 2.08 (brs, 3H), 3.88 (s, 2H), 4.48 (s, 2H), 7.38 (s app,

4H); LC–MS (APCI) m/z: 387 [MꢀH]^ꢀ; HRMS (FAB) m/z [M+H]⁺

calcd for C₂₃H₃₃O₃S: 389.2145, found: 389.2162; HPLC: t_R=3.10 min

(99%) in 10% H₂O/CH₃CN.

A solution of the corresponding sulfoxide derivative (1 equiv) in

CH₂Cl₂(10 mL) was treated with m-CPBA (2 equiv). The mixture

was stirred at RT and monitored by TLC. After completion, the mix-

ture was partitioned between CH₂Cl₂and 5% aq Na₂CO₃. The or-

ganic phase was washed with brine, dried over MgSO₄and concen-

trated in vacuo to give crude product. Purification using flash chro-

matography (EtOAc/CH₂Cl₂; gradient elution) yielded the title com-

pound (29–99%).

1-Adamantan-1-yl-2-(2,4-dichloro-phenylmethanesulfonyl)etha-

none (99): A white solid (18 mg, 29%); mp: 171–1738C; ¹H NMR

(270 MHz, CDCl₃): d=1.60–1.79 (m, 6H), 1.81 (d, J=2.7 Hz, 6H),

2.08 (brs, 3H), 4.08 (s, 2H), 4.77 (s, 2H), 7.28 (dd, J=8.1, 2.2 Hz,

1H), 7.47 (d, J=2.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H); LC–MS (APCI)

m/z: 399 [MꢀH]^ꢀ; HRMS (ESI) m/z [M+H]⁺calcd for C₁₉H₂₂Cl₂O₃S:

401.0739, found: 401.0745; HPLC: t_R=6.75 min (98%) in 10% H₂O/

MeOH.

N-[4-(2-Adamantan-1-yl-2-oxoethanesulfonyl)phenyl]acetamide

(92): Purification using flash chromatography (EtOAc/CH₂Cl₂; gradi-

ent elution) yielded the title compound as a white solid (79 mg,

81%); mp: 151–151.58C; ¹H NMR (270 MHz, CDCl₃): d=1.56–1.70

(m, 6H), 1.73 (d, J=2.7 Hz, 6H), 2.04 (brs, 3H), 2.22 (s, 3H), 4.27 (s,

2H), 7.43 (brs, 1H), 7.69 (dt, J=8.7, 2.2 Hz, 2H), 7.86 (dt, J=8.7,

2.2 Hz, 2H); LC–MS (APCI) m/z: 374 [MꢀH]^ꢀ; HRMS (FAB) m/z

[M+Na]⁺calcd for C₂₀H₂₅NO₄SNa: 398.1402, found: 398.1396;

HPLC: t_R=1.85 min (>99%) in 10% H₂O/CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethylsulfanyl)benzoic acid (100): A so-

lution of 1-adamantyl bromomethyl ketone (514 mg, 2.0 mmol) in

CH₃CN (20 mL) was treated with 3-mercaptobenzoic acid (340 mg,

2.1 mmol) followed by Et₃N (2 mL). The mixture was stirred at RT

overnight, partitioned between CH₂Cl₂and brine. The organic

phase was washed with brine, dried over MgSO₄and concentrated

in vacuo. Purification using flash chromatography gave the title

compound as a white solid (550 mg, 83%); mp: 129–1318C;

¹H NMR (270 MHz, CDCl₃): d=1.65–1.80 (m, 6H), 1.87 (d, J=2.7 Hz,

6H), 2.06 (brs, 3H), 4.00 (s, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.58 (dd,

J=7.7, 1.7 Hz, 1H), 7.91 (dd, J=7.7, 1.7 Hz, 1H), 8.01 (d, J=1.7 Hz,

1H); LC–MS (ESI) m/z: 329 [MꢀH]^ꢀ; HRMS (ESI) m/z [M+Na]⁺calcd

for C₁₉H₂₂O₃SNa: 353.1187, found: 353.1159; HPLC: t_R=1.12 min

(98%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(4-chloro-benzenesulfonyl)ethanone

(93):

Purification using flash chromatography (hexane/EtOAc; gradient

elution) yielded the title compound as a white crystalline solid

1

(52 mg, 64%); mp: 165–1668C; H NMR (270 MHz, CDCl₃): d=1.69

(m, 6H), 1.75 (d, J=2.8 Hz, 6H), 2.05 (brs, 3H), 4.28 (s, 2H), 7.53

(dt, J=7.6, 2.3 Hz, 2H), 7.88 (dt, J=7.5, 2.1 Hz, 2H); LC–MS (APCI)

m/z: 353 [M+H]⁺; HRMS (FAB) m/z [M+H]⁺calcd for C₁₈H₂₂ClO₃S:

353.0978, found: 353.0969; HPLC: t_R=3.42 min (>99%) in 20%

H₂O/CH₃CN.

3-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}-N-methylbenzamide

(101) The compound was prepared using method D. A white solid

(70 mg, 68% yield) was obtained; mp: 122–1238C; ¹H NMR

(270 MHz, CDCl₃): d=1.62–1.73 (m, 6H), 1.84 (d, J=2.7 Hz, 6H),

2.04 (brs, 3H), 3.00 (d, J=4.4 Hz, 3H), 3.96 (s, 2H), 6.14 (brs, 1H),

7.30 (d, J=7.7 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.7 Hz,

2H) and 7.72 (s, 1H); LC–MS (APCI) m/z: 342 [MꢀH]^ꢀ; HRMS (ESI)

m/z [M+H]⁺calcd for C₂₀H₂₆NO₂S: 344.1684, found: 344.1679;

HPLC: t_R=2.2 min (97%) in 10% H₂O/CH₃CN.

1-Adamantan-1-yl-2-(toluene-4-sulfonyl)ethanone (94): Purifica-

tion using flash chromatography (hexane/EtOAc; gradient elution)

yielded the title compound as a white crystalline solid (60 mg,

82%); mp: 146–147.58C; ¹H NMR (270 MHz, CDCl₃): d=1.53–1.74

(m, 12H), 2.04 (brs, 3H), 2.44 (s, 3H), 4.26 (s, 2H), 7.53 (d, J=

8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H); LC–MS (APCI) m/z: 331

[MꢀH]^ꢀ; HRMS (FAB) m/z [M+Na]⁺calcd for C₁₉H₂₄O₃SNa:

355.1344, found: 355.1344; HPLC: t_R=2.99 min (>99%) in 10%

H₂O/CH₃CN.

3-{[2-(Adamantan-1-yl)-2-oxoethyl]sulfanyl}-N,N-dimethyl benza-

mide (102): The compound was prepared using method D. A clear

oil (190 mg, 65% yield) was obtained; ¹H NMR (270 MHz, CDCl₃):

1-Adamantan-1-yl-2-(4-chloro-phenylmethanesulfonyl)ethanone

(95): A white solid (40 mg, 68%); mp: 166.5–167.58C; ¹H NMR

1042

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Adamantyl Ethanones as Potent 11b-HSD1 Inhibitors

[14] R. Fraser, M. C. Ingram, N. H. Anderson, C. Morrison, E. Davies, J. M. C.

Connell, Hypertension 1999, 33, 1364–1368.

[15] P. M. Stewart, C. B. Whorwood, Steroids 1994 , 59 , 9 0 –9 5.

[16] U. C. T. Oppermann, B. Persson, H. Jçrnvall, Eur. J. Biochem. 1997 , 249 ,

35 5 –3 60.

[17] J. R. Seckl, B. R. Walker, Endocrinology 2001 , 142 , 137 1 –1 376.

[18] P. M. Stewart, A. M. Wallace, R. Valentino, D. Burt, C. H. L. Shackleton,

C. R. W. Edwards, Lancet 1987, 2, 821–824.

[19] A. K. Agarwal, T. Mune, C. Monder, P. C. White, J. Biol. Chem. 1994, 269,

25959–25962.

d=1.65–1.76 (m, 6H), 1.83 (d, J=2.7 Hz, 6H), 2.03 (brs, 3H), 2.96

(s, 3H), 3.09 (s, 3H), 3.95 (s, 2H), 7.19–7.39 (s, 1H); LC–MS (APCI)

m/z: 356 [MꢀH]^ꢀ; HRMS (ESI) m/z [M+H]⁺calcd for C₂₁H₂₈NO₂S:

358.1841, found: 358.1819; HPLC: t_R=2.2 min (97%) 10% H₂O/

CH₃CN.

3-(2-Adamantan-1-yl-2-oxoethanesulfinyl)-N,N-dimethylbenza-

mide (103) and 3-(2-adamantan-1-yl-2-oxoethanesulfonyl)-N,N-

dimethylbenzamide (104):

A cold solution of 102 (177 mg,

0.33 mmol) in CH₂Cl₂(15 mL) was treated with m-CPBA (96 mg, 60–

77% purity). The mixture was stirred at ꢀ108C for 1.5 h, parti-

tioned between CH₂Cl₂and 5% aq Na₂CO₃. The organic phase was

washed with brine, dried over MgSO₄and concentrated in vacuo.

Purification using flash chromatography (EtOAc/CH₂Cl₂; gradient

elution) gave 103 as a clear oil (30 mg, 24%); ¹H NMR (270 MHz,

CDCl₃): d=1.65–1.80 (m, 12H), 2.02 (brs, 3H), 2.95 (s, 3H), 3.10 (s,

3H), 3.76 (d, J=15 Hz, 1H), 4.16 (d, J=15 Hz, 1H), 7.55 (d, J=

4.9 Hz, 2H), 7.68–7.75 (m, 2H); LC–MS (ESI) m/z: 374 [M+H]⁺;

HRMS (ESI) m/z [M+H]⁺calcd for C₂₁H₂₈NO₃S: 374.1790, found:

374.1776; HPLC: t_R=1.81 min (>99%) in 10% H₂O/CH₃CN. Com-

pound 104 was obtained as a clear oil (90 mg, 70%); ¹H NMR

(270 MHz, CDCl₃): d=1.58–1.72 (m, 12H), 2.03 (brs, 3H), 2.98 (s,

3H), 3.11 (s, 3H), 4.28 (s, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.72 (d, J=

7.7 Hz, 1H), 7.96–8.00 (m, 2H); LC–MS (ESI) m/z: 388 [MꢀH]^ꢀ;

HRMS (ESI) m/z [M+H]⁺calcd for C₂₁H₂₈NO₄S: 390.1739, found:

390.1726; HPLC: t_R=1.90 min (99%) in 10% H₂O/CH₃CN.

[20] E. Rask, T. Olsson, S. Sçderberg, R. Andrew, D. E. Livingstone, O. John-

son, B. R. Walker, J. Clin. Endocrinol. Metab. 2001 , 86 , 141 8 –1 421.

[21] K. Kannisto, K. H. Pietilꢃinen, E. Ehrenborg, A. Rissanen, J. Kaprio, A.

Hamsten, H. Yki-Jꢃrvinen, J. Clin. Endocrinol. Metab. 2004 , 89 , 441 4 –

4421.

[22] H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R.

Seckl, J. S. Flier, Science 2001 , 294 , 216 6 –2 170.

[23] E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, J. S. Flier,

Diabetes 2005 , 54 , 102 3 –1 031.

[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 , 1492 4 –1 4929.

[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 ,

93 1 –9 38.

[26] P. Alberts, L. Engblom, N. Edling, M. Forsgren, G. Klingstrçm, C. Larsson,

Y. Rçnquist-Nii, B. Ohman, L. Abrahmsꢄn, Diabetologia 2002, 45, 1528–

1532.

[27] P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norl-

ing, G. Klingstrçm, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M.

Fiedler, E. Bergqvist, B. Ohman, E. Bjçrkstrand, L. B. Abrahmsꢄn, Endocri-

nology 2003 , 144 , 475 5 –4 762.

[28] 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 , 51 7 –5 27.

[29] B. R. Walker, A. A. Connacher, R. M. Lindsay, D. J. Webb, C. R. W. Edwards,

J. Clin. Endocrinol. Metab. 1995 , 80 , 315 5 –3 159.

[30] R. C. Andrews, O. Rooyackers, B. R. Walker, J. Clin. Endocrinol. Metab.

2003 , 88 , 28 5 –2 91.

Acknowledgements

This work was supported by Sterix Ltd., a member of the Ipsen

Group. We thank Ms. A. C. Smith for technical assistance, Dr. N.

Muller and Dr. I. Viossat for the CYP inhibition and metabolic sta-

bility studies. We also thank the ESPRC national mass spectrome-

try service centre at the University of Wales (Swansea, UK) for

some high-resolution accurate mass measurements.

[31] M. Hawkins, D. Hunter, P. Kishore, S. Schwartz, M. Hompesch, G. Hollis,

R. Levy, B. Williams, R. Huber, Diabetes 2008, 57, A99–A100.

[32] J. W. Tomlinson, P. M. Stewart, Nat. Clin. Pract. Endocrinol. Metab. 2005 ,

1 , 9 2 –9 9.

[33] U. Oppermann, Endocr. Metab. Immune Disord. Drug Targets 2006, 6,

259–269.

Keywords: 11b-HSD1 · adamantyl ethanones · diabetes ·

hydroxysteroid dehydrogenase

syndrome

·

inhibitors

·

metabolic

[34] S. P. Webster, T. D. Pallin, Expert Opin. Ther. Pat. 2007 , 17 , 140 7 –1 422.

[35] K. A. Hughes, S. P. Webster, B. R. Walker, Expert Opin. Invest. Drugs 2008 ,

17 , 48 1 –4 96.

[1] S. M. Grundy, J. Clin. Endocrinol. Metab. 2004 , 89 , 259 5 –2 600.

[2] T. C. Sandeep, B. R. Walker, Trends Endocrinol. Metab. 2001, 12, 446–453.

[3] 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 , 83 1 –8 66.

[4] B. R. Walker, Diabetic Med. 2006 , 23 , 128 1 –1 288.

[5] R. Thieringer, A. Hermanowski-Vosatka, Expert Rev. Cardiovasc. Ther.

2005 , 3 , 91 1 –9 24.

[6] J. E. Friedman, J. S. Yun, Y. M. Patel, M. M. McGrane, R. W. Hanson, J. Biol.

Chem. 1993, 268, 12952–12957.

[36] X. Su, N. Vicker, B. V. L. Potter, Prog. Med. Chem. 2008 , 46 , 2 9 –1 30.

[37] C. G. Schnackenberg, Curr. Opin. Invest. Drugs 2008, 9, 295–300.

[38] C. Fotsch, M. H. Wang, J. Med. Chem. 2008 , 51 , 485 1 –4 857.

[39] C. Hale, M. Wang, Mini-Rev. Med. Chem. 2008 , 8 , 70 2 –7 10.

[40] C. D. Boyle, Curr. Opin. Drug Discov. Devel. 2008, 11, 495–511.

[41] T. Barf, J. Vallgꢅrda, R. Emond, C. Hꢃggstrçm, G. Kurz, A. Nygren, V. Lar-

wood, E. Mosialou, K. Axelsson, R. Olsson, L. Engblom, N. Edling, Y. Rçn-

quist-Nii, B. Ohman, P. Alberts, L. Abrahmsꢄn, J. Med. Chem. 2002 , 45 ,

381 3 –3 815.

[42] B. G. Bhat, N. Hosea, A. Fanjul, J. Herrera, J. Chapman, F. Thalacker, P. M.

Stewart, P. A. Rejto, J. Pharmacol. Exp. Ther. 2007 , 324 , 29 9 –3 05.

[43] 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 , 52 7 –5 32.

[7] M. Wang, Nutr. Metab. (Lond.) 2005, 2, 3.

[8] P. O. Hasselgren, Curr. Opin. Clin. Nutr. Metab. Care 1999 , 2 , 20 1 –2 05.

[9] 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 , 559 3 –5 602.

[10] B. S. McEwen, J. Clin. Endocrinol. Metab. 2002 , 87 , 194 7 –1 948.

[11] 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 ,

252 7 –2 533.

[44] C. Fotsch, M. D. Bartberger, E. A. Bercot, M. Chen, R. Cupples, M. Emery,

J. Fretland, A. Guram, C. Hale, N. H. Han, D. Hickman, R. W. Hungate, M.

Hayashi, R. Konlorowski, Q. Y. Liu, G. Matsumoto, D. J. S. Jean, S. Ursu,

M. Veniant, G. F. Xu, Q. P. Ye, C. Yuan, J. D. Zhang, X. P. Zhang, H. Tu,

M. H. Wang, J. Med. Chem. 2008 , 51 , 795 3 –7 967.

[12] J. W. Chu, D. F. Matthias, J. Belanoff, A. Schatzberg, A. R. Hoffman, D.

Feldman, J. Clin. Endocrinol. Metab. 2001 , 86 , 356 8 –3 573.

[13] M. Wamil, J. R. Seckl, Drug Discovery Today 2007 , 12 , 50 4 –5 20.

ChemMedChem 2010, 5, 1026 – 1044

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemmedchem.org

1043

B. V. L. Potter et al.

MED

[45] M. Henriksson, E. Homan, L. Johansson, J. Vallgꢅrda, M. Williams, E.

Bercot, C. H. Fotsch, A. Li, G. Cai, R. W. Hungate, C. C. Yuan, C. Tegley, D.

St. Jean, N. Han, Q. Huang, Q. Liu, M. D. Bartberger, G. A. Moniz, M. J.

Frizzle (Amgen Inc., USA; Biovitrum AB), PCT Application:

WO2005116002, 2005, p. 306.

Palm, M. Veniant, M. H. Wang, M. Williams, J. D. Zhang, J. Med. Chem.

2008 , 51 , 293 3 –2 943.

[53] C. Hale, M. Veniant, Z. L. Wang, M. Chen, J. McCormick, R. Cupples, D.

Hickman, X. S. Min, A. Sudom, H. D. Xu, G. Matsumoto, C. Fotsch, D. J.

Jean, M. H. Wang, Chem. Biol. Drug Des. 2008, 71, 36–44.

[46] C. Fotsch, J. Adams, M. Bartberger, E. A. Bercot, L. Cai, V. M. Castro, M.

Chen, R. Cupples, M. Emery, J. Fretland, A. Guram, S. Gustafsson, A.

Hague, C. Hale, N. Han, M. Hayashi, M. Henriksson, D. Hickman, E.

Homan, R. W. Hungate, L. Johansson, S. Jordan, C. Kaiser, R. Komorow-

ski, A. Li, Q. Liu, G. Matsumoto, K. McRae, G. Moniz, G. Palm, D. Pyring,

D. J. St.Jean, Jr., Y. Sun, M. Sydow-Backman, L. Tedenborg, H. Tu, S. Ursa,

M. Veniant, M. Williams, G. Xu, Q. Ye, C. Yuan, J. Zhang, X. Zhang, M.

Wang, Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT

(USA), March 22–26, 2009, MEDI-029.

[47] N. Vicker, X. D. Su, D. Ganeshapillai, A. Smith, A. Purohit, M. J. Reed,

B. V. L. Potter, J. Steroid Biochem. Mol. Biol. 2007 , 104 , 12 3 –1 29.

[48] X. D. Su, N. Vicker, D. Ganeshapillai, A. Smith, A. Purohit, M. J. Reed,

B. V. L. Potter, Mol. Cell. Endocrinol. 2006 , 248 , 21 4 –2 17.

[54] H. X. Wang, Z. M. Ruan, J. J. Li, L. M. Simpkins, R. A. Smirk, S. C. Wu, R. D.

Hutchins, D. S. Nirschl, K. Van Kirk, C. B. Cooper, J. C. Sutton, Z. P. Ma, R.

Golla, R. Seethala, M. E. K. Salyan, A. Nayeem, S. R. Krystek, S. Sheriff,

D. M. Camac, P. E. Morin, B. Carpenter, J. A. Robl, R. Zahler, D. A. Gordon,

L. G. Hamann, Bioorg. Med. Chem. Lett. 2008 , 18 , 316 8 –3 172.

[55] D. Q. Sun, Z. L. Wang, Y. M. Di, J. C. Jaen, M. Labelle, J. Ma, S. C. Miao, A.

Sudom, L. Tang, C. S. Tomooka, H. Tu, S. Ursu, N. Walker, X. L. Yan, Q. P.

Ye, J. P. Powers, Bioorg. Med. Chem. Lett. 2008 , 18 , 351 3 –3 516.

[56] L. D. Julian, Z. W. Wang, T. Bostick, S. Caille, R. Choi, M. DeGraffenreid,

Y. M. Di, X. He, R. W. Hungate, J. C. Jaen, J. S. Liu, M. Monshouwer, D.

McMinn, Y. Rew, A. Sudom, D. Q. Sun, H. Tu, S. Ursu, N. Walker, X. L. Yan,

Q. P. Ye, J. P. Powers, J. Med. Chem. 2008 , 51 , 395 3 –3 960.

[57] H. Tu, J. P. Powers, J. S. Liu, S. Ursu, A. Sudom, X. L. Yan, H. D. Xu, D. Mei-

ninger, M. DeGraffenreid, X. He, J. C. Jaen, D. Q. Sun, M. Labelle, H. Ya-

mamoto, B. Shan, N. P. C. Walker, Z. L. Wang, Bioorg. Med. Chem. 2008 ,

16 , 892 2 –8 931.

[58] Y. Rew, D. L. McMinn, Z. L. Wang, X. He, R. W. Hungate, J. C. Jaen, A.

Sudom, D. Q. Sun, H. Tu, S. Ursu, E. Villemure, N. P. C. Walker, X. L. Yan,

Q. P. Ye, J. P. Powers, Bioorg. Med. Chem. Lett. 2009 , 19 , 179 7 –1 801.

[59] J. Xiang, M. Ipek, V. Suri, M. Tam, Y. Xing, N. Huang, Y. Zhang, J. Tobin,

T. S. Mansour, J. McKew, Bioorg. Med. Chem. Lett. 2007, 17, 4396–4405.

[60] N. Vicker, X. Su, F. Pradaux, M. J. Reed, B. V. L. Potter (Sterix Limited, UK),

PCT Application: WO2006100502, 2006, p. 225.

[49] D. J. Hosfield, Y. Q. Wu, R. J. Skene, M. Hilgers, A. Jennings, G. P. Snell, K.

Aertgeerts, J. Biol. Chem. 2004 , 280 , 463 9 –4 648.

[50] J. R. Patel, Q. Shuai, J. Dinges, M. Winn, M. Pliushchev, S. Fung, K.

Monzon, W. Chiou, J. H. Wang, L. P. Pan, S. Wagaw, K. Engstrom, F. A.

Kerdesky, K. Longenecker, R. Judge, W. Y. Qin, H. M. Imade, D. Stolarik,

D. W. A. Beno, M. Brune, L. E. Chovan, H. L. Sham, P. Jacobson, J. T. Link,

Bioorg. Med. Chem. Lett. 2007 , 17 , 75 0 –7 55.

[51] C. Yuan, D. J. Jean, Q. Y. Liu, L. Cai, A. W. Li, N. H. Han, G. Moniz, B.

Askew, R. W. Hungate, L. Johansson, L. Tedenborg, D. Pyring, M. Wil-

liams, C. Hale, M. Chen, R. Cupples, J. D. Zhang, S. Jordan, M. D. Bart-

berger, Y. X. Sun, M. Emery, M. H. Wang, C. Fotsch, Bioorg. Med. Chem.

Lett. 2007 , 17 , 605 6 –6 061.

Received: February 25, 2010

Revised: April 12, 2010

[52] L. Johansson, C. Fotsch, M. D. Bartberger, V. M. Castro, M. Chen, M.

Emery, S. Gustafsson, C. Hale, D. Hickman, E. Homan, S. R. Jordan, R. Ko-

morowski, A. W. Li, K. McRae, G. Moniz, G. Matsumoto, C. Orihuela, G.

Published online on May 18, 2010

1044

www.chemmedchem.org

ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2010, 5, 1026 – 1044

Article Doi

Discovery of adamantyl ethanone derivatives as potent 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors

DOI: 10.1002/cmdc.201000081

Source and publish data:

Authors:

Article abstract of DOI:10.1002/cmdc.201000081

Full text of DOI:10.1002/cmdc.201000081

Products guided by the article

R&D Labs maybe for 1224598-29-1

Relevant to this article

Hot Product