Discovery and structure-activity relationships of pentanedioic acid diamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type I

Article abstract of DOI:10.1016/j.bmcl.2009.03.140

Benzylamides of pentanedioic acid were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC₅₀s on the 1

Full text of DOI:10.1016/j.bmcl.2009.03.140

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2674–2678
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and structure–activity relationships of pentanedioic acid diamides
as potent inhibitors of 11b-hydroxysteroid dehydrogenase type I
Didier Roche a, Denis Carniato a, , Caroline Leriche a,à, Franck Lepifre a, Serge Christmann-Franck a,
Ulrich Graedler b, Christine Charon a, Sophie Bozec a, Liliane Doare a,
Fabien Schmidlin a,§, Marc Lecomte a, Eric Valeur a,–
,
*
a Merck-Serono, 4 Avenue du Président Mitterrand, 91380 Chilly-Mazarin, France
b Merck-Serono, Frankfurterstrasse 250, 64293 Darmstadt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzylamides of pentanedioic acid were identified as inhibitors of 11b-hydroxysteroid dehydrogenase
type 1 (11b-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors
with single digit nanomolar IC50s on the 11b-HSD1 human isoform. The hydroxy adamantyl amide lead
compound was selective against 11b-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and
Received 12 February 2009
Revised 26 March 2009
Accepted 27 March 2009
Available online 1 April 2009
displayed good inhibition of 11b-HSD1 (IC50 < 0.1
l
M) in a cellular model (3T3L1 adipocytes).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pentanedioic acid diamides
11b-Hydroxysteroid dehydrogenase type I
inhibitors
Rational drug design
Lead optimisation
Hydroxysteroid dehydrogenases are a family of enzymes that
regulate ligand-binding to various steroid hormone receptors at
the pre-receptor level, like a switch, converting steroid hormones
to the inactive or precursor forms and vice-versa.1 Among these,
11b-hydroxysteroid dehydrogenases 1 and 2 are enzymes modify-
ing glucocorticoid chemistry, oxidizing the 11b-hydroxyl position
or reducing the 11-oxo group, which determines whether or not
steroids are able to bind to glucocorticoid (and mineralocorticoid)
receptors.2 Glucocorticoid receptor binding is restricted to active
steroids with 11b-hydroxyl moiety, that is, mainly cortisol in
humans and corticosterone in rodents. 11b-hydroxysteroid dehy-
drogenase type 2 (11b-HSD2) is expressed in tissues containing
the mineralocorticoid receptor, predominantly kidney, but also
gut and placenta.3 11b-HSD2 inactivates active glucocorticoids
(such as cortisol and corticosterone) to cortisone or 11-dehydro-
corticosterone.2 On the other hand, the isoform 11b-hydroxyster-
oid dehydrogenase type 1 (11b-HSD1) activates inert precursors
(cortisone, 11-dehydrocorticosterone) to active glucocorticoids by
11-oxoreductase activity in liver, adipose tissue, brain, skeletal
muscle, vascular smooth muscle cells and other organs.4 Several
in vivo models and studies have documented the physiological
importance of this glucocorticoid converting enzyme in insulin ac-
tion. In particular, 11b-HSD1 knockout mice were shown to resist
to hyperglycemia and to have increased hepatic insulin sensitiv-
ity.5 In mirror of this, 11b-HSD1 overexpression in mouse adipose
tissue resulted in development of visceral adiposity, hyperglyce-
mia and insulin resistance.6 In addition, 11b-HSD2 overexpression
in mouse adipose tissue, leading to the inactivation of glucocorti-
coids, improved glucose tolerance and insulin sensitivity.7
This body of evidence strongly suggest that 11b-HSD1 inhibi-
tion is a potential therapeutic target for a broad range of disorders
that could be improved by decreased intracellular glucocorticoid
levels (i.e., cortisol), including the obesity-induced metabolic syn-
drome. Selectivity against the 11b-HSD2 isoform is expected to
be crucial as deficiency or inhibition (i.e., licorice) of 11b-HSD2
are conditions allowing mineralocorticoid receptor to be occupied
by cortisol, leading to the ‘‘essential” form of hypertension.8 There-
fore, many efforts towards the discovery and development of selec-
tive 11b-HSD1 inhibitors have been carried out.9 In this report we
describe such a new class of inhibitors.
* Corresponding author.
E-mail address: serge.christmann-franck@merck.fr (S. Christmann-Franck).
Present address: Cytomics Pharmaceuticals, 86 rue de Paris, Bâtiment Mélèze,
91400 Orsay, France.
Compound 1 derived from glutaric anhydride was identified
as an initial hit by high-throughput screening. This compound
displayed an interesting level of potency on the human isolated
à
Present address: Fovea Pharma, 3-5 Impasse Reille, 75014 Paris, France.
Present address: Ipsen, 5 Avenue du Canada, 91966 Les Ulis Cedex, France.
Present address: Novartis Pharma AG, FAB 16-4.06.6 CH-4002 Basel, Switzerland.
§
–
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.140

D. Roche et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2674–2678
2675
R1
R1
R1
R2
O
O
R1
R5
N
NH
OH
+
N
(a)
H
N
H
N
OH
R4
R2
H
N
O
O
O
O
O
O
O
R4
R5
R2 R3
(b)
R2 R3
OH
N
Scheme 1. Reagents and conditions: Et3N, toluene, heat.
R4
NH2
R1
R1
O
O
Cl
NH2
(c)
H
H
O
N
OH
N
R4
N
H
O
N
N
O
O
R2 R3
N
O
R2 R3
F
1
R4
IC50 = 1.2 µM
MW = 327 Da
Scheme 2. Reagents and conditions: (a) DCC, HOBt, THF, HNR4R5, rt; (b) DCC, HOBt,
DMF, rt; (c) DMF, heat.
Figure 1. Initial hit discovered by HTS.
11b-HSD1 (IC50 = 1.2
(MW = 327 Da) (Fig. 1).
l
M) with regard to its small size
Table 2
Variations on the 2-adamantyl-amide
H
Due to the simplicity of the scaffold, a large collection of amines
was used to prepare libraries of amides and explore rapidly the SAR
around the R1,R2 variations (Scheme 1).
R
N
O
However the levels of inhibition obtained after screening these
libraries were disappointing (selected data in Table 1). Further-
more, the activity of the benzylamide derivatives could not be con-
firmed (compounds 3 and 4, Table 1). As anticipated based on the
known hydrophobic nature of the 11b-HSD1 ligand binding pocket,
the most active compounds were derived from hydrophobic bicy-
clic amines such as decahydroquinoline and 2-adamantyl amines
(compounds 13 and 14). The decreased activity of the correspond-
ing 1-adamantyl regioisomer 12 underlined the requirement of
both a perfect shape match and the presence of a hydrophobic
group in this pocket to achieve high potency.
Therefore, efforts were focused on new analogues based on a
pentanedioic 2-amino-N-(adamantan-2-yl) amide scaffold. To fur-
ther explore the SAR, the free carboxylic acid moiety was replaced
with an amide or an oxadiazole. The oxadiazole derivatives were
prepared in 2 steps from the corresponding carboxylic acids
according to Scheme 2. Amides appeared far superior to carboxylic
acid derivatives in terms of potency (Table 2). Aromatic amides
a
Compounds
R
h 11b-HSD1 IC50 (nM)
BEIb
18.8
H
N
15
17
O
F
H
N
16
17
19
9
18.3
19.0
O
O
OCH3
H
N
H
N
18
19
48
18
17.2
18.2
O
O
OCH3
F
Table 1
Variations of the amide substituents
H
N
O
O
R1
OH
N
N
H
N
R2
20
21
22
16
9
19.0
21.5
16.4
Compounds
R1NR2
h-HSD1% inhibition at 1 l
Ma
O
O
2
3
4
5
2-Cl-Ph-NH
2-Cl-Bn-NH
2,4-diCl-Bn-NH
cHex-CH2–NH
0
H
N
22
27
7
6
7
cHex-NH
4-Cl,3-pyr-NH
13
0
N
8
9
4-OCH3, 3-pyr-NH
N-Me-piperazine
7-(2-Methyl)-indole-NH
3-Pyr-CH2–NH
1-Adamantyl-NH
Decahydroquinoline
2-Adamantyl-NH
7
0
0
11
8
N
N
160
10
11
12
13
14
O
O
34
50b
23
48
19.6
a
IC50 values were only determined for compounds displaying >50% inhibition at
M.
This compound exhibited an IC50 of 1800 nM.
1
l
b
(continued on next page)

2676
D. Roche et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2674–2678
Table 2 (continued)
presence of a chain-constraining group was clearly necessary to
BEIb
20.1
achieve potency, as the unsubstituted analogue 25 failed to show
satisfactory inhibition. This evidence was further supported by
docking studies which showed an orientation of the pentanoic
chain towards the hydrophobic pocket exploited by other 11b-
HSD1 inhibitors (Fig. 2).
Amide replacement with the oxadiazole bioisoster led to potent
11b-HSD1 inhibitors, compounds 30 and 31 being the most potent
with respective IC50 of 12 and 8 nM and an improved BEI. However,
optimisation of these compounds was not pursued due to their
poor metabolic stability (data not shown).
Although the adamantyl group has been used quite often in the
synthesis of bioactive molecules,12 its high hydrophobicity renders
it prone to oxidation in living organism, which could lead to a rapid
elimination of the drug. However, substituted-adamantanes have
been used recently to prepare metabolically stable 11b-HSD1
a
Compounds
R
h 11b-HSD1 IC50 (nM)
H
N
24
60
O
O
H
N
25
26
27
28
29
30
>1000
150
340
200
57
—
H
N
20.5
17.4
15.6
18.3
22.1
22.5
O
O
O
H
N
N
N
Cl
N
N
N
O
O
O
N
N
12
N
N
31
8
a
11b-HSD1 enzyme activity was assessed in 30 mM Hepes buffer, pH 7.4, con-
substrate mixture cortisone/NADPH
M). Reaction was initiated by addition of 3 g of human recombinant
taining 1 mM EDTA, 1 mM G-6P, and
(200 nM/200
a
l
l
11b-HSD1 expressed in E. coli and terminated with addition of 18b-glycyrrhetinic
acid stop solution after 150 min incubation at 37 °C. Determinations of cortisol
levels were monitored by HTRF assay (Cisbio International).
b
Binding efficiency index = pKi or pIC50/molecular weight (kDa), pIC50 was used
in this study.
such as 4-fluoro-phenyl 15, 4-fluoro-benzyl 19 or pyridine ana-
logue 20 all showed a 2 log improvement in potency, with the best
member of the series achieving 9 nM (2-methoxy-phenyl deriva-
tive 17). Interestingly, amides derived from sec- and tert-alkyl
amines remained in the same range of activity (compounds 21–
24), with compound 21 reaching the same potency and a better
Binding Efficiency Index10 (BEI) due to a smaller molecular weight
when compared to the most potent aromatic amide (compound
17). In this optimisation program, BEI was consistently considered
to identify and focus on chemical functionalities carrying the
strongest binding contributions.
Despite the high potency of aromatic amides, aliphatic deriva-
tives were preferred due to the potential toxicity of the aniline
group, these N-alkyl derivatives possessing the additional advan-
tage of improving the physico-chemical properties.
Furthermore, the unsubstituted, gem-dimethyl and cyclohexyl
derivatives 25–27 were prepared in order to explore the influence
of the R2/R3 linker substitution (hydrophobic interaction and/or
conformational effect through Thorpe-Ingold restriction).11 The
Figure 2. View of the already published steroid substrate binding site of human
11b-HSD1 (PDB code 2ILT)15 with (a) the adamantane sulfone compound from the
experimental structure and (b) docked compound 34; for the sake of clarity, only
Thr124, Tyr177 and catalytic residues Ser170 and Tyr183, and only polar hydrogen
atoms have been displayed; colour coding by atoms is as follows: oxygen in red,
nitrogen in blue, hydrogen in white, fluorine in light blue, chlorine in light green,
phosphorus in orange; carbon atoms are coloured in light orange for the
experimental ligand (a), in green for compound 34 (b), in light yellow for the
protein and in light blue for the NADP(H) cofactor (protonation state not
determined in the X-ray structure).

D. Roche et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2674–2678
2677
Table 4
Table 3
Profile of the two lead compounds
Substituted adamantane derivatives
Compounds
33
34
Compounds Structures
h 11b-HSD1
IC50 (nM)
BEI
a
b
a
h 11b-HSD1 IC50
m 11b-HSD1 IC50
r 11b-HSD1 IC50
m 11b-HSD1 3T3L1 cellular IC50
h 11b-HSD2 IC50
h 11b-HSD2/HSD1 IC50 selectivity ratio
Water solubility
8 nM
10 nM
31 nM
<1
>10
>1250
491 g/mL
0.6 h
10%
3.3 L/h/kg
3.1 L/kg
24% (iv) 50% (po)
<20%
8 nM
88 nM
980 nM
<0.1
>10
>1250
597 g/mL
1.2 h
30%
1.8 L/h/kg
2.7 L/kg
20% (iv) 22% (po)
40%
a
H
N
H
N
a
b
O
l
l
M
M
lM
lM
32
>1000
—
c
O
O
O
HO
H
N
H
N
l
l
d
Plasma t1/2
O
Fd
33
34
8
8
21.6
23.3
O
CLd
H2N
Vssd,e
RFf
H
N
H
N
h SPBg
HO
O
O
a
h 11b-HSD1 experimental protocol as described in Table 2; for murine (m) or
rat (r) 11b-HSD1, 2.5 lg of microsome fractions from liver (Tebu) were used in the
H
N
H
assay.
N
b
3T3L1 cells were differentiated (5 days) in adipocytes and cultured (4 days) in a
24 well plate format before incubation with test compounds (10À5–10À7 M) for
150 min. Cortisol in the culture supernatant was then measured for 11b-HSD1
activity in HTRF assay (see Table 2).
35
550
18.0
O
O
HO
c
11b-HSD2 enzyme activity was assessed in 50 mM Tris buffer, pH 7.8, con-
a
h 11b-HSD1 experimental protocol as described in Table 2.
BEI as described in Table 2.
taining 1 mM MgCl2, 0.5 mM NAD, and 1
expressed in E. coli. Reaction was initiated by addition of cortisol 20 nM and ter-
minated with addition of carbenoxolone 10 M stop solution after 60 min incu-
lg of human recombinant 11b-HSD2
b
l
bation at room temperature. Determinations of cortisol levels were monitored by
HTRF assay (Cisbio International).
d
Dosed i.v. (0.2 mg/kg) and p.o. (0.5 mg/kg) in male rats in a low dose cocktail
inhibitors13,12c and DPP-4 inhibitors14 suitable for oral administra-
tion. We therefore explored the influence of substituting the ada-
mantane ring on the potency, physicochemical properties and
metabolic stability of our best compounds.
study; mean values over 3 rats.
e
Volume of distribution at steady state.
Recovery of unchanged drug in feces (0–24 h collection).
f
g
Human serum protein binding.
Gratifyingly, not only the activity of the naked adamantyl com-
pound 26 was preserved, but it was improved with the trans-car-
boxamide and trans-hydroxy isomers 33 and 34 (Table 3). In
comparison, the cis-hydroxy isomer 35 was moderately active
while the carboxylic acid adamantyl was inactive.
lar model (3T3L1 adipocytes), exhibited a decent PK profile and
therefore looks promising for in vivo evaluation. Further optimisa-
tion of this compound is currently ongoing.
In order to investigate the influence of the hydroxy substituent of
the adamantane on potency, compound 34 was docked in the al-
ready published human 11b-HSD1–adamantane sulfone co-crystal
structure (PDB code 2ILT)15 and results are depicted in Figure 2.16
The carbonyl of the adamantyl-amide established hydrogen bonds
with hydroxyl groups of residues Ser170 and Tyr183, while the ada-
mantane occupied the same position in compound 34 docking pose
and in the ligand from the original crystal structure. In addition to its
potential influence on PK properties, the hydroxyl group carried by
the adamantyl group contributed to the binding of compound 34
to the protein through a hydrogen bond with residue Thr124. As a
consequence, compound 34 was identified as the compound having
the best binding efficiency in this series (BEI of 23.3).
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