Adamantyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Article abstract of DOI:10.1016/j.bmcl.2005.06.040

Adamantyl triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.

Full text of DOI:10.1016/j.bmcl.2005.06.040

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4359–4362
Adamantyl triazoles as selective inhibitors
of 11b-hydroxysteroid dehydrogenase type 1
Steven Olson,a,* Susan D. Aster,a Kai Brown,b Linda Carbin,b Donald W. Graham,a
Anne Hermanowski-Vosatka,b Cheryl B. LeGrand,b Steven S. Mundt,b
Michael A. Robbins,a James M. Schaeffer,b Llnon H. Slossberg,a Michael J. Szymonifka,a
Rolf Thieringer,b Samuel D. Wrightb and James M. Balkoveca
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Atherosclerosis and Endocrinology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 20 May 2005; revised 8 June 2005; accepted 10 June 2005
Available online 21 July 2005
Abstract—Adamantyl triazoles were identified as selective inhibitors of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1).
They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure–activity relationships of these
inhibitors are presented.
Ó 2005 Elsevier Ltd. All rights reserved.
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1)
is an endoplasmic reticulum-associated enzyme that acts
as an NADPH-dependent reductase and converts inac-
tive cortisone to the active glucocorticoid cortisol.1 As
such, it is a regulator of intracellular cortisol concentra-
tion and has been implicated in a number of metabolic
sequela of increased glucocorticoid tone: visceral adi-
posity, high blood pressure, elevated fasting glucose,
and dyslipidemia.1,2
Scheme 1. Interconversion of cortisone and cortisol.
The complement of 11b-HSD1 is the structurally related
11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2),
an NAD-dependent dehydrogenase that catalyzes the
inactivation of cortisol by conversion to cortisone
(Scheme 1).1,3 11b-HSD2 is expressed in cells that con-
tain the mineralocorticoid receptor (MR) and protects
the MR from illicit occupation by cortisol.4
and enhance cognitive function in both healthy elderly
men and type
diabetics.7 Since inhibition of
11b-HSD2 is known to result in hypokalemia, sodium
retention, and hypertension,3,4 the invention of selective
11b-HSD1 inhibitors is an important area of academic
and pharmaceutical research.8
2
Adamantyl triazole 1 was identified as a potent and
selective inhibitor of 11b-HSD1 by high-throughput
screening. It was determined to have an IC50 versus
human 11b-HSD1 of 7.8 nM (98 nM for mouse)
using a SPA-based assay.9 In the human 11b-HSD2
counterscreen, the compound had an IC50 of
>3000 nM (>10,000 nM for mouse).
Carbenoxolone is a drug developed in the 1960s for the
treatment of digestive tract ulcers, but it has recently
found attention as a potent but nonspecific inhibitor4c,5
of both 11b-HSD1 and 11b-HSD2. In the past few
years, it has been shown that carbenoxolone can im-
prove insulin sensitivity in men with type 2 diabetes6
A
pharmacodynamic mouse model of 11b-HSD1
Keywords: 11b-HSD1; Adamantyl triazole; Metabolic syndrome.
Corresponding author. Tel.: +1 732 594 4831; fax: +1 732 594
9545; e-mail: steven_olson@merck.com
inhibition was developed to measure the in vivo activity
of the inhibitors. In this model, a test compound is
*
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.040

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S. Olson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4359–4362
dosed orally (10 mg/kg), and after a prescribed time
interval, [3H]cortisone is injected intravenously via the
tail vein. After 2 min, blood is collected by cardiac punc-
ture. Steroids are then extracted from the serum and
analyzed by HPLC. The relative levels of [3H]cortisone
and [3H]cortisol are measured, and a percent inhibition
is calculated. In the case of 1, the compound inhibited
59% of [3H]cortisone conversion 1 h after dosing and
17% of conversion 4 h after dosing relative to untreated
control animals. This powerful assay of 11b-HSD1
activity was an important driver of the SAR. Moreover,
1 has been shown to have positive therapeutic effects in
mouse models of obesity, diabetes, and atherosclerosis,
showing that the pharmacodynamic activity may play
a role in the etiology of metabolic syndrome.10
Substitution on the adamantane fragment was explored
using a similar synthetic method (Scheme 3).12 Interest-
ingly, the 2-substitued adamantyl triazole 913 had simi-
lar activity as the corresponding 1-substituted analog,
1, suggesting that the active site can accommodate con-
siderable differences in the orientation the adamantane.
Unfortunately, additional substituents on the adaman-
tane led, generally, to poorer activity. The most polar
compound in the series, 3-hydroxyadamantyl triazole
14, was a particularly poor inhibitor with a 100-fold loss
in activity relative to the unsubstituted adamantyl tria-
zole 1 (see Table 2).
The lack of a clear SAR for the adamantyl fragment
contrasted with the clear relationship between ring size
and activity on the eastern half. It was postulated that
this trend toward improved potency may be due to the
increased hydrophobicity found in the larger rings rath-
er than an intrinsic preference for a specific ring size. To
that end, a series of acyclic analogs was synthesized
which kept the overall hydrophobicity constant while
varying the attached groups (18–21). For acyclic amides,
methyl triflate was the reagent of choice for the forma-
tion of the methyl imino ethers. Disappointingly, the
reaction of these imino ethers with adamantane-1-carbo-
hydrazide using the previously optimized conditions
gave significant amounts of oxadiazole as an unwanted
byproduct (Scheme 4).
Triazole 1 was prepared in 80% yield by the condensa-
tion of adamantyl-1-carbohydrazide and the imino ether
of caprolactam,11 and analogs were readily prepared by
this method, starting with lactams of varying ring size
(Scheme 2). The imino ether was formed using Meerw-
einÕs salt and then coupled to the adamantyl-substituted
acyl hydrazide. The in vitro activity of this series (Table
1) showed a strong correlation to the number of methyl-
enes in the starting lactam with 7 (n = 7) being the most
potent inhibitor. The 12-membered ring compound 8
(n = 8) shows a slight drop-off in activity, but it is still
an excellent inhibitor. It appears that the active site is
quite accommodating to large hydrophobic substituents.
The murine pharmacodynamic activity, on the other
hand, initially increases with the size of the ring, but
plateaus with 4 and slowly decreases for the largest
compounds. The implication is that the compounds with
larger rings suffer from poor pharmacokinetics, and
their intrinsic potency becomes less relevant.
Improving the selectivity of this reaction proved diffi-
cult. However, it was found that the oxadiazole could
be directly converted to the triazole in the presence of
excess amine.16 To take advantage of this reaction,
the synthetic sequence was redesigned (Scheme 5).
Adamantane-1-carbohydrazide was acylated with an
Scheme 2. Synthesis of adamantyl triazoles.
Table 1. Activity of adamantyl triazoles by ring size
Compound
n
IC50 (nM)a
Mouse pharmacodynamic
assay (% inhibitionb)
Human
11b-HSD1
Mouse
11b-HSD1
Human
11b-HSD2
Mouse
11b-HSD2
1 h
4 h
2
3
1
4
5
6
7
8
1
2
3
4
5
6
7
8
2180
278
7.8
2.2
4
6820
1112
98
2000
>3000
>3000
787
10,000
>10,000
>4000
ꢀ10,000
4563
0
—
59
83
43
69
45
17
0
—
17
24
44
31
29
3
16
8
30
25
2.5
1.4
3.6
4.6
2.2
9.2
ꢀ4000
11,650
>4000
8.7
358
a Most values were determined by a single seven point titration with 4-fold dilutions. To establish the reliability of the data, compound 1 was tested
>30 times. Its human and mouse 11b-HSD1 values and standard deviation were 7.8 2.7 and 98 28 nM, respectively.
b Relative to control.

S. Olson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4359–4362
4361
to improve the metabolic stability of the eastern half
of the molecule, two phenyl-containing analogs were
prepared using the route shown in Scheme 4. The benzyl
analog 22 has a hydrophobicity similar to that of the
eight-membered ring analog 4. As predicted from the
SAR, the IC50 of 22 is also similar to 4. Unfortunately,
the pharmacodynamic activity of 22 was not improved,
possibly because the benzylic methylene is a metabolic
liability. The phenyl analog 23 possesses a hydrophobic-
ity and mouse 11b-HSD1 activity comparable to 1, but
its pharmacodynamic activity is significantly improved,
suggesting improved pharmacokinetics for this analog.
Further optimization studies will be reported in due
course.
Scheme 3. Synthesis of triazoles with substituted adamantanes.
acid chloride in the presence of triethylamine to give an
N-acetyl hydrazide. This intermediate was converted to
the imidoyl chloride and cyclized to give the oxadiazole.
Finally, the oxadiazole was heated in a sealed tube with
the trifluoroacetate salt of a primary amine to provide
the desired triazole.
The activities for this series of isomeric inhibitors (18–
21) are shown in Table 3. The IC50s vary moderately
with no clearly evident trend, and it seems that the en-
zyme is relatively undiscerning for small alkyl substitu-
ents of equal polarity. Given their similarity to 1, it is
not surprising that these compounds have comparable
pharmacodynamic activity. In this series, the N-propyl
analog, 20, is the most potent with 37% inhibition at
the 4 h timepoint, whereas the N-ethyl compound, 19,
performs quite poorly in the PD assay. In an attempt
In summary, a novel class of potent and selective inhib-
itors of mouse and human 11b-HSD1 has been identi-
fied. In addition, in vivo 11b-HSD1 inhibitory activity
in a mouse pharmacodynamic model has been demon-
strated. The initial pharmacological results imply that
increasing the hydrophobicity of the inhibitors generally
results in a corresponding improvement of 11b-HSD1
inhibition, but this progression is often counterbalanced
by poor performance in the pharmacodynamic assay.
Table 2. SAR of substituted adamantyl triazoles
Compound
R
IC50 (nM)
Mouse pharmacodynamic
assay (% inhibition)
Human
11b-HSD1
Mouse
11b-HSD1
Human
11b-HSD2
Mouse
11b-HSD2
1 h
4 h
9
10
2-Adamantyl
7.7
13
35
104
118
365
292
1674
417
587
50
>4000
2550
>4000
>10,000
>4000
>4000
>4000
>4000
>4000
>4000
>2000
42
—
—
7
24
—
—
0
3,5-Dimethyladamantyl
3,5,7-Trimethyladamantyl
3-Phenyladamantyl
3-Bromoadamantyl
3-Hydroxyadamantyl
3-Fluoroadamantyl
Adamantylmethyl
11
12
180
2.3
23
>4000
23
13
>4000
>4000
>4000
>4000
17,600
—
—
—
0
—
—
—
7
14
739
37
1514
16
74
36
1715
3,5-Dimethyladmantylmethyl
—
—
Scheme 4. Initial synthesis of triazoles from acyclic imino ethers.
Scheme 5. Improved synthesis of triazoles from acyclic imino ethers.

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S. Olson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4359–4362
Table 3. SAR of n-alkyl-substituted adamantyl triazoles
Compound
R1
R2
IC50 (nM)
Mouse pharmacodynamic
assay (% inhibition)
Human
11b-HSD1
Mouse
11b-HSD1
Human
11b-HSD2
Mouse
11b-HSD2
1 h
4 h
18
19
20
21
22
23
Methyl
Ethyl
Butyl
Propyl
Ethyl
11
52
11
72
3
91
50
2840
<4000
>4000
>4000
92
>4000
>4000
50
31
24
55
—
48
85
21
5
Propyl
Butyl
23
37
—
23
47
Methyl
Benzyl
Phenyl
270
14
>4000
>4000
>4000
Methyl
Methyl
37
109
>4000
˚
8. (a) Barf, T.; Vallgarda, J.; Emond, R.; Ha¨ggstro¨m, C.;
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Replacing the alkyl substituents on the eastern half of
the molecule with a phenyl group, as in 23, enhances
pharmacodynamic activity without changing the overall
polarity of the inhibitor. Additional optimization of
these lead compounds may eventually lead to a treat-
ment strategy for metabolic syndrome.
¨
´
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scintillation proximity assay (SPA). Tritiated-cortisone,
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HSD1 from CHO transfectants at 37 °C to allow conver-
sion to cortisol to progress. Following incubation, a
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scintillation counter. This is similar to the method
described in Ref. 8a.
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