Bioorganic & Medicinal Chemistry Letters
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,
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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
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Corresponding author. Tel.: +34 934 024 533.
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.