Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold

Article abstract of DOI:10.1016/j.bmcl.2015.07.097

The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomer

Full text of DOI:10.1016/j.bmcl.2015.07.097

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4250–4253
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 11b-HSD1 inhibitors: C-1 versus C-2 substitution and effect of
the introduction of an oxygen atom in the adamantane scaffold
Rosana Leiva a, Constantí Seira b, Andrew McBride c, Margaret Binnie c, F. Javier Luque b,
Axel Bidon-Chanal b, Scott P. Webster c, Santiago Vázquez a,
⇑
a Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona
E-08028, Spain
b Departament de Fisicoquímica, Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain
c Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, EH16 4TJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The adamantane scaffold is found in several marketed drugs and in many investigational 11b-HSD1 inhi-
bitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demon-
strate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred
over the substitution at C-1 and is necessary for potency at human 11b-HSD1. Furthermore, the introduc-
tion of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11b-HSD1 inhibition.
Molecular modeling studies provide a basis to rationalize these features.
Received 6 July 2015
Revised 27 July 2015
Accepted 29 July 2015
Available online 5 August 2015
Keywords:
Adamantane
Ó 2015 Elsevier Ltd. All rights reserved.
11b-HSD1 inhibitors
Drug discovery
Molecular modeling
Adamantane is a very common building block in medicinal
chemistry.1 So far, seven adamantane derivatives have been
introduced in clinical use for a variety of diseases and molecular
targets (Fig. 1) and hundreds of derivatives have been tested
against different targets.
Interestingly, the rapid inspection of the structures of the
adamantane derivatives shown in Figure 1 reveals as a general
trend that the polycyclic scaffold is substituted at the C-1 position.
Of note, the anti-influenza A activity of amantadine is significantly
higher than that of its isomer, 2-aminoadamantane.2
In recent years, more than 25 pharmaceutical companies have
been working on the synthesis of 11b-hydroxysteroid dehydroge-
nase type 1 (11b-HSD1) inhibitors, as a potential new candidates
for the treatment of type II diabetes and metabolic syndrome.3
On the one hand, contrary to the aforementioned trend observed
in clinically approved adamantanes, most of the 11b-HSD1 inhibi-
tors evaluated are 2-adamantyl substituted derivatives (Fig. 2).4,5
However, for these derivatives no comparison between the activi-
ties of compounds substituted at the C-1 and C-2 positions is avail-
able. On the other hand, a potential advantage of positioning the
substituent at the 1-position is that one of the metabolically labile
positions of the adamantane would be blocked. Also, for any given
substituent, the theoretical clogP value of the 1-substituted analog
is usually lower than that of the 2-substituted derivative.6
The synthesis and pharmacological evaluation of a series of 1-
adamantyl amide 11b-HSD1 inhibitors has been previously
reported by Webster et al.7 Of note, inhibitors 1 and 2 were found
to be equipotent compounds (Fig. 3). Later, Xia et al. reported that
the C-2 substituted amide 3 was 20 times more potent than its 1-
isomer, 4 (Fig. 3).8
Taking into account these seemingly contradictory results and
the scarcity of data on 1-substituted adamantane derivatives eval-
uated as 11b-HSD1 inhibitors,5 we decided to synthesize a small
series of 1- and 2-adamantyl derivatives featuring fragments of
proven inhibitors of 11b-HSD1 in order to compare their pharma-
cological behavior.
Moreover, considering that very few heteroadamantanes have
been biologically tested as 11b-HSD1 inhibitors,9 we also evaluated
some 1- and 5-substituted 2-oxaadamantanes. The introduction of
an oxygen atom in the scaffold increases the polar surface area and
decreases the overall lipophilicity. Thus, if potency is retained, the
lipophilic ligand efficiency, which is one of the most significant
parameters that normalizes potency relative to lipophilicity, would
increase.10
We started from known urea 5, an 11b-HSD1 inhibitor reported
by Vitae.11 In our microsomal assay, 5 was shown to be a submi-
cromolar inhibitor of the human 11b-HSD1 enzyme
⇑
Corresponding author. Tel.: +34 934 024 533.
E-mail address: svazquez@ub.edu (S. Vázquez).
http://dx.doi.org/10.1016/j.bmcl.2015.07.097
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

R. Leiva et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4250–4253
4251
O
NH2
Rimantadine
N
N
NH2
NH2
Amantadine
1
2
O
Memantine
H
O
S
N
CO2H
N
O
N
S
O
O
Cl
O
O
Cl
O
O
N
H
N
H
N
4
3
O
Tromantadine
Adapalene
Figure 3. Structures of 11b-HSD1 inhibitors 1–4.
OH
OH
O
Taking into account the aforementioned results and that the
corresponding C-2 isomers of 8 and 9 had not been previously
tested, we synthesized both amides from 2-aminoadamantane.
By way of contrast with the lack of inhibitory activity of their C-
1 isomers, amides 12 and 13 displayed potent, nanomolar inhibi-
tion. Also, in agreement with the previous trend observed in going
from ureas 6 and 7 to their corresponding amides 9 and 10, the
novel amide 12 was more potent than our previous hit 5. It was
noteworthy that ring contraction from 12 to 14 led to a less potent
inhibitor.
N
N
N
H
H2N
Saxagliptin
CN
O
NC
Vildagliptin
Figure 1. Clinically-approved adamantane derivatives. Amantadine, rimantadine
and tromantadine are anti-virals, the first two are M2 channel blockers and are
anti-Influenza drugs, and tromantadine inhibits herpex virus simplex replication;
memantine is a NMDA receptor antagonist used in the treatment of Alzheimer’s
disease; adapalene inhibits keratinocyte differentiation and proliferation and is
used for the treatment of acne; and saxagliptin and vildagliptin are DPP-IV
inhibitors used to treat type 2 diabetes.
Overall, for the three pairs of isomers evaluated here, substitu-
tion in position 2 of the adamantyl scaffold consistently leads to
more potent inhibitory activity of human 11b-HSD1.
The introduction of an oxygen atom in the adamantane does not
improve the activity within the series of the C-1 substituted
derivatives. As Ye et al. found, within a series of 2,2-disubstituted
adamantanes, that the corresponding oxaadamantane analogs per-
formed poorly,9b we have not evaluated oxaadamantane
derivatives with the amino group attached to a methylene group
of the polycyclic ring.16
In order to rationalize these results we combined docking stud-
ies with molecular dynamics simulations to examine the structural
integrity of the binding of compounds 5, 6, and 12. Let us note that
the inhibitory activities of 5 and 6, which only differ in the substi-
tution at positions C1 and C2, vary from 87% (5) to 3% (6). On the
other hand, compound 12 involves the replacement of the piperi-
dine moiety present in 5 by the cyclohexyl one in 12, leading to
a moderate increase of the inhibitory activity from 87% (5) to
100% (12).
Compounds were docked in the binding cavity of human 11b-
HSD1 using Glide.17 In all cases the best scored poses mimicked
the binding mode of PF-877423 (Fig. S1 in Supporting information),
which is a potent adamantyl-based inhibitor against the human
(IC50 = 0.87
of inhibition of human 11b-HSD1 at 10
pounds. The IC50 value of the more potent derivatives is also
included.
All the compounds were synthesized in medium to high yields
using standard chemistry from four known amines: amantadine
(1-aminoadamantane),
l
M). Table 1 shows the structures and the percentage
l
M of the novel com-
2-aminoadamantane,
5-amino-2-ox-
aadamantane,12 and 3-methyl-2-oxaadamantane-1-amine13 (see
details in Supplementary material). Briefly, the reaction of aman-
tadine with 1-piperidinecarbonyl chloride in dichloromethane in
the presence of triethylamine furnished, after column chromatog-
raphy, urea 6 in 31% yield.14 In the same way, starting from the
known 3-methyl-2-oxaadamante-1-amine, urea 7 was obtained
in 34% yield. We also synthesized amides 8 and 9 in high yields,
by reaction of amantadine with 3,5-dichloro-4-aminobenzoic acid
or cyclohexanecarboxylic acid, respectively.15
Surprisingly, in our microsomal assay ureas 6 and 7 and amide 8
did not inhibit the human 11b-HSD1 enzyme. Under the same con-
ditions, amide
9 only inhibited 20% the enzyme activity.
Oxaadamantanes 10 and 11 were also very poor inhibitors.
H
CO2H
N
H
N
N
S
N
H
CO2H
N
H
N
O
N
N
O
MK-544
AZD6925
AZD8329
S
O
H
N
H
N
H
N
N
N
N
S
SO2
O
O
O
O
F
H2NOC
O
H2NOC
N
HO
F
HIS-388
KR-67105
H2NOC
UI-1499
N
H
N
NH
N
O
N
N
N
N
O
N
N
H2NOC
SAR184841
ABT-384
CF3
Figure 2. Selected adamantyl-based 11b-HSD1 inhibitors.

4252
R. Leiva et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4250–4253
Table 1
Structures and human 11b-HSD1 inhibitory activities of compounds 5–14
Product
11b-hHSD1 inhibition
11b-
at 10
l
Ma
hHSD1IC50
(nM)a
H
N
N
5
6
87
873
ND
O
O
3
N
N
H
O
O
7
8
0
0
ND
ND
N
N
H
O
Cl
N
H
NH2
Cl
O
9
20
9
ND
ND
N
H
Figure 4. Last snapshot of a representative molecular dynamics simulation for the
complexes between human 11b-HSD1 and compounds PF-877423 (top left), 6 (top
right), 12 (bottom left) and 5 (bottom right). In all cases residues Tyr183 and
Ser170, the NADP cofactor and the ligand are represented as sticks and only the
polar hydrogens are shown. The shape of the binding cavity is shown as a white
contour.
O
O
10
N
H
O
showed a larger RMSD (2.5–3.7 Å) due to the enhanced flexibility
of the loops that enclose the binding pocket.
11
12
9
ND
86
N
O
H
The hydrogen bond formed between the inhibitor and the
hydroxyl group of Ser170 was retained in all cases (average dis-
tance of 2.8 Å). Often, an additional hydrogen bond with the hydro-
xyl unit of Tyr183 was transiently formed. Nevertheless,
compound 6 consistently showed a higher root-mean square fluc-
tuation (1.4 Å) compared to inhibitors 5 and 12 (RMSF of 0.8 Å),
suggesting a poorer fit of the hydrophobic cage in the binding cav-
ity due to the change in the substitution pattern from position C1
in 6 to position C2 in 5 and 12. This reflects the larger steric hin-
drance of the adamantyl cage with the NADP nicotinamide ring
arising from the C1-substitution, because C2-derived compounds
are found to adopt a configuration where the C2-H unit is primarily
oriented toward the nicotinamide ring (Fig. 4)
H
N
100
O
Cl
NH2
Cl
H
13
14
86
76
74
N
O
H
N
520
O
Finally, the moderate increase in the inhibitory activity of com-
pound 12 relative to 5 may be ascribed to the enhanced hydropho-
bicity afforded by the cyclohexane unit, as noted in their respective
clogP values of 4.5 and 3.6, determined from quantum mechanical
IEF/MST continuum solvation calculations.19 This trend agrees with
similar findings reported for series of structurally related
compounds.20
In conclusion, bearing in mind the aforementioned pharmaco-
logical results, it is clear that for potent 11b-HSD1 inhibitory activ-
ity, 2-substituted adamantanes are preferred over their
corresponding 1-substituted counterpart. Also, the introduction
of an oxygen atom in the polycyclic scaffold did not improve the
activity (compare 9 vs 10 and 11).
a
11b-HSD1 inhibition was determined in mixed sex, Human Liver Microsomes
(Celsis In-vitro Technologies) by measuring the conversion of 3H-cortisone to 3H-
cortisol in cortisol-Scintillation Proximity Assay. Percentage inhibition was
a
determined relative to a no inhibitor control.
enzyme (Ki = 1.4 nM).18 Thus, all the compounds retained the
hydrogen bond formed between the carbonyl oxygen of the
amide/urea moiety with the hydroxyl group of Ser170 and the ada-
mantyl cage filled a common site in the binding pocket.
Three independent 50 ns MD simulations were run for each
ligand–receptor complex, and additional runs were performed for
the complex with PF-877423, which was used as a reference sys-
tem. All the simulations were stable except that of the complex
with the C1-substituted compound 6, since the ligand was released
from the binding site in one simulation. Upon exclusion of this lat-
ter trajectory, the root-mean square deviation (RMSD) profiles
were similar in all cases. Thus, the RMSD of the protein backbone
varied from 1.5 to 2.2 Å, whereas the residues in the binding site
Acknowledgments
R.L. thanks the Ministerio de Educación, Cultura y Deporte for a
PhD Grant (FPU program). We thank financial support from
Ministerio de Economía y Competitividad (Project SAF2014-57094-
R) and the Generalitat de Catalunya (Grants 2014-SGR-00052 and

R. Leiva et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4250–4253
4253
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