Evaluation of selective inhibitors of 11β-HSD1 for the treatment of hypertension

Article abstract of DOI:10.1016/j.bmcl.2013.03.011

In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway.

Full text of DOI:10.1016/j.bmcl.2013.03.011

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3650–3653
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of selective inhibitors of 11b-HSD1 for the treatment
of hypertension
David R. Bauman a, , Alan Whitehead b, , Lisa C. Contino c, Jisong Cui a, Margarita Garcia-Calvo d, Xin Gu b,
Nancy Kevin b, Xiuying Ma c, Lee-yuh Pai c, Kashmira Shah c, Xiaolan Shen e, Sloan Stribling c,
b,
Hratch J. Zokian d, Joe Metzger c, Diane E. Shevell a, , Sherman T. Waddell
⇑
⇑
a Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
b Department of Cardiovascular Disease, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
c Department of Drug Metabolism, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
d Department of In Vitro Sciences, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
e Lab Animal Resources, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials
with 11b-HSD1 inhibitors, we examined a set of 11b-HSD1 inhibitors in a series of relevant in vitro and
in vivo assays. Select 11b-HSD1 inhibitors reduced blood pressure in our preclinical models but most or
all of the blood pressure lowering may be mediated by a 11b-HSD1 independent pathway.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 December 2012
Revised 23 February 2013
Accepted 4 March 2013
Available online 22 March 2013
Keywords:
11b-HSD1
Hypertension
1,2,4-Triazoles
11b-HSD1-KO
Spontaneous hypertensive rat
Metabolic Syndrome is a complex multifaceted condition char-
acterized by dyslipidemia, hypertension, increased visceral adipos-
ity and loss of glycemic fitness.1 Simultaneous incremental
elevations in these individual risk factors sharply increase the risk
of cardiovascular disease and recent mouse studies have suggested
a link between intracellular cortisol (in rodents, corticosterone)
levels and the development of Metabolic Syndrome-like pheno-
type.2 Within key metabolic tissues which express the glucocorti-
coid receptor (GR), such as liver and adipose, levels of the
metabolically active hormone cortisol (which is a ligand for GR)
are amplified by the conversion of the inactive precursor cortisone
(in rodents, 11-dehydrocorticosterone) to cortisol by type 1 11b-
hydroxysteroid dehydrogenase (11b-HSD1). Recently, 11b-HSD1
knock-out (KO) mice fed a high fat diet resisted the development
of Metabolic Syndrome whereas overexpression of 11b-HSD1 in
mouse adipose tissue led to a Metabolic Syndrome-like phenotype
that resulted in hypertension, presumably due to reduced intracel-
lular 11-dehydrocorticosterone and increased intracellular cortico-
sterone levels.2 In contrast to 11b-HSD1 which increases cortisol
levels, the type 2 11b-HSD (11b-HSD2) enzyme converts cortisol
to inactive cortisone and can therefore decrease cortisol levels.3
This is important in tissues that express the mineralocorticoid
receptor (MR) such as kidney, in which intracellular cortisol (an
MR ligand) concentrations are sharply reduced. This pre-receptor
regulation of intracellular cortisol levels by 11b-HSD2 is critical
for protecting the MR from excessive cortisol. The importance of
11b-HSD2 is further evidenced by mouse and human genetic vari-
ants; loss of 11b-HSD2 function led to a phenotype with apparent
mineralocorticoid excess characterized by hypertension, hypokale-
mia and reduced plasma rennin activity.4 Taken collectively,
11b-HSD1 represents a target for therapeutic agents that would
selectively inhibit 11b-HSD1 and a potential pathway for the treat-
ment of diseases characterized by Metabolic Syndrome.
Two highly potent and selective inhibitors of 11b-HSD1 were
discovered in our laboratories.5 Compounds 1 (MK-0736) and 2
(MK-0916), have been the recent subject of two Phase IIa proof
of concept trials in patients with type 2 diabetes and Metabolic
Syndrome (Fig. 1).6 Interestingly, while having only a small effect
on endpoints associated with glycemic fitness, 1 and 2 produced
a statistically significant decrease in blood pressure in the treat-
ment groups.7 These early clinical results focused our efforts on
⇑
Corresponding authors. Tel.: +1 732 594 5364 (D.E.S.).
E-mail addresses: diane_shevell@merck.com (D.E. Shevell), tim_waddell@-
merck.com (S.T. Waddell).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.011

D. R. Bauman et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3650–3653
3651
F3C
F3C
Cl
F3C
F3C
F3C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
F
N
O
N
N
EtO2S
EtO2S
F
EtO2S
4
F
3
1
2
3
2
5
6
N
F
O
Me
Figure 1. Selected inhibitors of 11b-HSD1 based on blood-pressure lowering effects in SHR model.
hydroxyamidine. To develop a radio-labeled 11b-HSD1 compound,
the ubiquitous aryl group on the right hand side provided a strate-
gically sound position for the introduction of a bis-iodinated aryl
group (Scheme 2). To streamline the synthesis of the radio-labeled
precursor, the left-hand oxadiazole was first installed starting from
9 using the same 4-step procedure en route to methyl amide 11.
The requisite iodinated aryl group was prepared in a straight-
forward process starting from 12 through the regioselective intro-
F
F
O
HO
N
N
N
CF3
1.
2.
N
N
N
N
a-d
Me
N
CF3
O
Me
Me
5
7
O
CO2Me
O
e-g
OMe
h-k
Me
N
H
H2N
F
N
F
HO2C
N
9
10
11
duction of iodide
a to the aniline nitrogen with subsequent
HO
N
Me
O
manipulation en route to 13. Conversion of the acid to the reactive
o-trifluoroaryl tetrazole 14 enabled coupling of the sterically con-
gested chloroimidate intermediate of 11 to proceed, albeit in mod-
est yield, producing bis-iodo 15 as a precursor for radio-labeling.11
Finally, tritium was introduced by action of Pd/C in the presence of
T2, yielding tracer [3H]-5 with a specific activity of 40.3 Ci/mmol.
For the discovery program that produced compounds 1–6, rou-
tine screening for HSD potency and selectivity was accomplished
using a functional SPA assay employing microsomes isolated from
stable cell lines expressing human 11b-HSD1 or 11b-HSD2 and
measuring the production of radiolabeled cortisol from radiola-
beled cortisone. The data set provided by this assay allowed for
the identification of compounds that both potently and selectively
inhibited 11b-HSD1 as compared to 11b-HSD2, among them 3–6
(Table 1). To confirm that these compounds directly interacted
with 11b-HSD1 a radiometric direct binding assay was developed
using rat liver microsomes with [3H]-5. Binding was specific, satu-
rable and consistent with a single molecular site (data not shown).
The radiometric binding data indicated that [3H]-5 potently bound
to 11b-HSD1 with nanomolar affinity (Kd = 11 nM) and that the
Scheme 1. Reagents and conditions: (a) CDI, NHþ4 OHꢀ, DCM, 96%; (b) trichlorotri-
azine, DMF, 62%; (c) NH2OH, EtOH, 100 °C, 98%; (d) MeCF2CO2H, PyBroB, DIEA, DCM,
then reflux, 62%; (e) CDI, NHþ4 OHꢀ DCM, 86%; (f) trichlorotriazine, DMF, 80%; (g)
NH2OH, EtOH, 90 °C, 98%; (h) MeCF2CO2H, PyBroB, DIEA, DCM, then reflux, 66%; (i)
KOH, MeOH, 98%; (j) (COCl)2, DMF, DCM, then MeNH2, 56%.
investigating blood pressure lowering following 11b-HSD1 inhibi-
tion, in order to identify better 11b-HSD1 inhibitors for the treat-
ment of hypertension. In this study, we examined two structural
subclasses of 11b-HSD1 inhibitors, one which was very effective
at lowering systolic blood pressure (SBP) in the spontaneously
hypertensive rat (SHR) model and the other which was only mod-
estly effective at lowering SBP. These compounds had similar
in vitro potencies and total exposure levels in SHR plasma. Of par-
ticular interest was the question of whether differential tissue
exposure (e.g., brain exposure) was responsible for this difference
in lowering blood pressure.
In a recent report, the synthesis and in vitro/in vivo data for the
class of sulfones exemplified by 1 and 4 were detailed.8 The prep-
aration of these compounds builds upon the functionally differen-
tiated adamantyl synthon 9, in a manner similar to the strategy for
5 outlined in Scheme 1.9 For the synthesis of 5, beginning with the
already installed right-hand 1,2,4-triazole7,10 installation of the
1,2,4-oxadiazole was achieved in an efficient 4-step sequence end-
ing in the coupling of difluoropropionic acid with a transient N-
number of liver binding sites (Bmax
)
was approximately
55,500 fmol/mg, which is consistent with its high expression level
in liver (mRNA and protein) (data not shown). Inhibition constants
(Ki) for 3–6 were determined using a radiometric competition as-
say and indicated that these compounds potently bound to 11b-
N
CF3
O
CF3 HN
CF3
O
a-c
N
d-f
OH
N
OMe
I
I
H2N
I
14
13
I
12
O
F3C
g
N
N
Me
N
H
F
F
F
N
14
N
N
F
I
Me
Me
O
N
N
Me
O
I
11
15
F3C
F3C
N
N
N
N
F
h
F
F
F
N
Me
N
N
Me
N
I
T
Me
Me
O
N
O
N
I
T
15
[3H]-5
Scheme 2. Reagents and conditions: (a) Ag2SO4, I2, EtOH, 91%; (b) KI, NaNO2, I2, CH3CN, 2M aq HCl, 86%; (c) NaOH, MeOH, 45 °C, 99%; (d) CDI, NH4OH, DCM, 93%; (e) cyanuric
chloride, DMF, 78%; (f) NaN3, ZnCl2, DMF, 61%; (g) (i) (ClCO)2, DMF, DCM, (ii) Compound 14, PhCH3, reflux, 21%; (h) Pd/C, Pd/CaCO3, T2.

3652
D. R. Bauman et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3650–3653
Table 1
ing data indicated similar total plasma peak concentrations be-
Biochemical properties of the 11b-HSD1 inhibitors
tween the low and high effect compounds. However, trough level
differences were identified whereby high effect compounds had
slightly to significantly higher total concentrations at trough time
points compared to the low effect compounds (Table 2).
Compound Human
11b-HSD2;
Human
11b-HSD1;
IC50 (nM)
Human IC50
(11b-HSD2/
11b-HSD1)
Rat 11b-
HSD1;
IC50 (nM)
Rat
Ki
(nM)
IC50 (nM)
3
4
5
6
>4000
>4000
3100
31.2
7.5
30.4
3.0
>128
>530
102
9.1
6.0
4.5
3.0
13.1
3.9
7.0
One explanation for the difference in BP efficacy was that sus-
tained exposure is needed to maintain lower BP. However, the high
effect compound 6 had the lowest free drug plasma concentration,
suggesting that plasma drug exposure (total or free drug) was a
poor indicator of BP efficacy. A second hypothesis tested was that
brain exposure might be necessary for a substantial antihyperten-
sive effect. Consequently, we set out to determine if there was a
difference in brain exposure between the high and low effect com-
pounds. Susceptibility to PGP was measured, and as indicated in
Table 2, the high effect compounds were not PGP substrates (BA/
AB ratio = 1.5 for 5 and 0.7 for 6), whereas the low effect compound
tested was a PGP substrate (BA/AB ratio = 10.2 for 4), consistent
with the idea that the high effect compounds might have greater
brain exposures. To verify that brain exposure differences existed
between low and high effect compounds, rats were dosed with
10 mg/kg compound, sacrificed at the indicated time, the brains
isolated, and a detailed PK study was performed for 3–6 (Table 2).
The resulting data gave brain to plasma ratios consistent with the
idea that the high effect compounds were not PGP substrates
(Brain/Plasma ratio >1 for 5 and 6) and that the low effect com-
pounds were PGP substrates (Brain/Plasma ratio <1 for 3 and 4).
Comparing total brain drug exposure between the two classes ap-
peared to support the idea that brain coverage was important for
the observed in vivo efficacy difference; however, more detailed
PK analyses indicated similar free drug levels in brain for both
2200
732
1.3
Change in Systolic BP (mm Hg)
10
0
Vehicle Control
3, 10 mg/kg/day
4, 10 mg/kg/day
5, 10 mg/kg/day
6, 10 mg/kg/day
-10
-20
-30
0
1
2
3
4
5
6
7
Time (Days)
Figure 2. SHR changes in systolic blood pressure treated with 11b-HSD1 inhibitors
for 7-days.
HSD1 with values similar to the functional enzyme inhibition (SOL-
SPA) data (Table 1).
Selectively potent inhibitors of 11b-HSD1 were tested in the
SHR model to determine in vivo hemodynamic profiles. SHR were
telemeterized with abdominal aorta catheters, dosed daily with
10 mg/kg compound and hemodynamic parameters recorded
(heart rate, systolic and diastolic blood pressure). After several
days of dosing, 3–6 significantly lowered both systolic and diastolic
BP in SHRs compared to vehicle treated animals (Fig. 2).
These compounds did lower heart rate in SHR and some of these
compounds did increase body weight (data not shown). Closer
analysis of the SHR data revealed that compounds could be differ-
entiated based on BP efficacy into two groups: low and high effect
compounds. On average, the low effect compounds (represented by
3 and 4) typically lowered SBP in the range of 3-8 mmHg in SHR,
while the high effect compounds (represented by 5 and 6) lowered
SBP by more than 15 mmHg in SHR. Although all of these com-
pounds had similar in vitro biochemical properties, they exhibited
very distinct in vivo efficacies in SHR, suggesting that some other
biophysical property was different between the two groups (low
vs high effect compounds), yet similar within each group (high
vs high effect compounds). Several hypotheses were tested to
investigate this in vivo BP efficacy difference.
low (3, 1.3 lM; 4, 0.5 lM) and high (5, 3 lM; 6, 0.08 lM) effect
compounds. Since unbound drug levels drive receptor occupancy,
this suggested that central exposure was not the main driver in
the observed BP efficacy difference.
To directly explore the origin of the observed BP lowering with
our 11b-HSD1 inhibitors, 5 was tested in telemeterized 11b-HSD1
KO mice. Interestingly, in the complete 11b-HSD1 KO a reduction
in baseline hemodynamic parameters was observed for SBP (KO
120 1.1 mmHg vs WT 127 1.4 mmHg), DBP (KO 91 1.0 mmHg
vs WT 98 0.9 mmHg) and heart rate (KO 585 4 bpm vs WT
595 6 bpm), although body weight (KO 30 0.6 g vs WT
29 0.4 g) and activity (KO
8
1.1 counts/min vs WT
7
0.4 counts/min) were similar between the two genotypes. As
the KO mice and WT controls are not littermates, this data does
not prove that loss of 11b-HSD1 lowers BP, but suggests a role
for 11b-HSD1 in blood pressure regulation.
Subsequently, 11b-HSD1 KO and WT animals were dosed with 5
to determine if the additional BP lowering effect observed in SHR
for high effect compounds was due to an off-target activity. As seen
in Figure 3, 5 had similar effects on SBP lowering in both 11b-HSD1
WT (ꢀ8 mmHg) and KO (ꢀ5.8 mmHg) mice with similar exposure
The first hypothesis tested was that PK differences were the
underlining cause for the BP efficacy difference. After compound
administration, plasma drug exposures were determined at peak
(ꢁ4 h post dose) and trough (ꢁ24 h post dose) for 3–6. The result-
(WT = 12.1 lM and KO = 13.1 lM for 5), indicating that most or all
of the BP lowering ability of high effect compounds was due to an
Table 2
Plasma and brain exposure for the 11b-HSD1 inhibitors
Compound
Time (h)
Plasma total (
l
M)
Plasma free (lM)
Brain total (
l
M)
Brain free (lM)
CSF (
lM)
PGP ratio
3
4
24
4
24
4
24
4
27.7 5.4
10.2 4.2
24.2 2.6
6.0 4.2
25.0 1.1
25.4 1.6
13.9 1.7
12.1 2.3
8.0 2.5
2.1 1.1
3.1 0.6
0.8 0.2
5.0 0.8
0.5 0.1
0.2 0.1
1.3 0.2
0.2 0.2
3.0 0.2
2.4 0.7
2.1 0.5
0.7 0.4
5.1 1.2
0.7 0.5
4.4 1.0
3.4 2.2
0.2 0.2
0.2 0.1
10.2
10.2
N/D
N/D
1.45
1.45
0.7
4
5
6
9.5 1.2
1.9 1.2
2.5 0.6
2.4 0.5
0.07 0.02
0.05 0.01
0.7 0.4
60.5 6.9
55.4 5.9
44.4 11.7
39.1 3.8
0.08 0.03
0.06 0.01
24
0.7

D. R. Bauman et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3650–3653
3653
suggests that BP lowering for this series of compounds operates
through an unknown off-target mechanism.
Change in Systolic BP (mm Hg)
10
5
WT, Vehicle
WT, 5, 30 mg/kg/day
KO, Vehicle
KO, 5, 30 mg/kg/day
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0
-5
-10
0
1
2
3
4
5
6
7
8
9 10 11
Time (Days)
Figure 3. 11b-HSD1 KO and WT mice changes in systolic blood pressure treated
with compound 5 for 11-days.
unknown off-target activity. In addition the decrease in HR and in-
crease in BW observed with 5 also appears to be off-target.
In an effort to better understand BP lowering observed in the
clinic after treatment with 11b-HSD1 inhibitor drugs, we studied
two sets of potent, selective adamantyl triazole inhibitors of 11b-
HSD1, which differed in their ability to reduce BP in the SHR model.
Since the ‘high BP effect’ compounds were not substrates for PGP
whereas the ‘low BP effect’ compounds were PGP substrates, a
leading hypothesis at the beginning of this study was that central
(brain, CNS) coverage of 11b-HSD1 might be necessary for the anti-
hypertensive effect. Although total brain levels were higher for the
‘high BP effect’ compounds, free-drug brain levels measured for
both classes were similar, leading to the conclusion that it is unli-
kely that central coverage is the main driver of the antihyperten-
sive effect.
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mice. Significant reductions in 11b-HSD1 KO mice baseline hemo-
dynamic profiles suggest an 11b-HSD1 dependent pathway in BP
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HSD1 KO and WT mice, the BP reduction difference observed in
SHR between high and low effect compounds is most likely due
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