Piperazine sulfonamides as potent, selective, and orally available 11β-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model

Article abstract of DOI:10.1021/jm8004948

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11β-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11β-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11β-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.

Full text of DOI:10.1021/jm8004948

4068
J. Med. Chem. 2008, 51, 4068–4071
Letters
Scheme 1a
Piperazine Sulfonamides as Potent, Selective,
and Orally Available 11ꢀ-Hydroxysteroid
Dehydrogenase Type 1 Inhibitors with
Efficacy in the Rat Cortisone-Induced
Hyperinsulinemia Model
Jason Xiang,*,† Zhao-Kui Wan,† Huan-Qiu Li,†
Manus Ipek,† Eva Binnun,† Jill Nunez,† Lihren Chen,†
John C. McKew,† Tarek S. Mansour,† Xin Xu,‡ Vipin Suri,§
May Tam,§ Yuzhe Xing,§ Xiangping Li,§ Seung Hahm,§
James Tobin,§ and Eddine Saiah†
a Conditions: (a) Hunig’s base, DMF, 85%; (b) TFA, CH2Cl2, 95%; (c)
ArSO2Cl, Hunig’s base, CH2Cl2, 75-90%.
different expression profiles: 11ꢀ-HSD1 is highest in liver,
adipose, and the central nervous system, whereas 11ꢀ-HSD2,
is expressed in kidney, colon, and other tissues.2
Chemical and Screening Sciences, Drug Safety and Metabolism, and
CardioVascular and Metabolic Diseases, Wyeth Research, 200
CambridgePark DriVe, Cambridge, Massachusetts 02140
A potential role for 11ꢀ-HSD1 inhibitors in metabolic disease
has been established using transgenic mice. Mice overexpressing
11ꢀ-HSD1 in adipose or liver show several features of metabolic
syndrome.3a,b On the other hand, 11ꢀ-HSD1 knockout mice are
resistant to diet-induced obesity and exhibit improved insulin
sensitivity and lipid profiles.3c Administration of specific 11ꢀ-
HSD1 inhibitors in mouse models of insulin resistance led to
improved hyperglycemia and insulin sensitivity.4,5 Recent
studies with the nonspecific 11ꢀ-HSD1 inhibitor carbenoxolone
also show improved hepatic insulin sensitivity and decreased
glucose production in humans.6 However, the 11ꢀ-HSD2
inhibitory activity of carbenoxolone is a limiting factor because
it induces renal mineralocorticoid excess at higher doses.6
Disruption or mutation in the 11ꢀ-HSD2 gene results in sodium
retention, hypokalemia, and hypertension.7 Therefore, while
inhibition of 11ꢀ-HSD1 is an attractive strategy for the design
of therapeutics for metabolic syndrome, it is ideal to have 11ꢀ-
HSD1 inhibitors to be selective against 11ꢀ-HSD2.
Several publications reported potent and selective 11ꢀ-HSD1
inhibitors.8 This report describes the SAR, PK, ex vivo activity,
and in vivo efficacy of a series of piperazine sulfonamides. Early
in our 11ꢀ-HSD1 program, piperazine sulfonamide 5a was
identified through HTS as a potent lead compound.9 Our
screening approach was to use a cell-based assay to assess all
new analogues, thus increasing the chances that active com-
pounds will also be cell permeable and potentially more
druglike.
Pyridylpiperazine sulfonamides were prepared via the route
shown in Scheme 1. Piperazine 3 was prepared by heating tert-
butylpiperazine 1-carboxylate 1 and 2-chloro-3-trifluorometh-
ylpyridine 2 in the presence of Hu¨nig’s base. Deprotection of
the tert-butyl carbamate was carried out using TFA to provide
the intermediate pyridylpiperazine 4. Final products 5 were
obtained in excellent yield by sulfonylation of the piperazine 4
with various arylsulfonyl chlorides. Phenylpiperazine sulfona-
mides were prepared via the route shown in Scheme 2.
Intermediate phenylpiperazine 7 was prepared from 2-bromo-
5-fluorobenzotrifluoride 6 and tert-butylpiperazine 1-carboxylate
1 via Buchwald amination. Removal of the carbamate and
sulfonylation of the resulting piperazine provided final phe-
nylpiperazine sulfonamide 9. Preparation of phenyl 2-(R)-
methylpiperazine sulfonamides is depicted in Scheme 3. In this
case, unprotected 2-(R)-methylpiperazine 10 was used directly
ReceiVed April 25, 2008
Abstract: 11ꢀ-Hydroxysteroid dehydrogenase type 1 (11ꢀ-HSD1) is
the enzyme that converts cortisone to cortisol. Evidence suggests that
selective inhibition of 11ꢀ-HSD1 could treat diabetes and metabolic
syndrome. Presented herein are the synthesis, structure-activity
relationship, and in vivo evaluation of piperazine sulfonamides as 11ꢀ-
HSD1 inhibitors. Through modification of our initial lead 5a, we have
identified potent and selective 11ꢀ-HSD1 inhibitors such as 13q and
13u with good pharmacokinetic properties.
The dramatic increase in the prevalence of type 2 diabetes
and obesity in recent years has led to an increased recognition
of “metabolic syndrome”, a collection of metabolic and
cardiovascular abnormalities. Metabolic syndrome is character-
ized by abdominal obesity, impaired glucose tolerance, dys-
lipidemia, low levels of high density lipoprotein (HDLa),
cholesterol, and hypertension.1 Recent investigations have
implicated aberrant glucocorticoid receptor (GR) signaling in
the development of several phenotypes associated with metabolic
syndrome. Glucocorticoid hormones are key metabolic regula-
tors. The major activator of the GR in humans is cortisol, and
the adrenal cortex is the major source of circulating cortisol.
GR signaling depends not only on the circulating cortisol levels
but also on the intracellular generation of cortisol through
reduction of cortisone, the inactive glucocorticoid.2 The reduc-
tion reaction is catalyzed by 11ꢀ-hydroxysteroid dehydrogenase
type 1 (11ꢀ-HSD1) with the concomitant oxidation of NADPH,
while cortisone itself is generated by the action of 11ꢀ-
hydroxysteroid dehydrogenase type 2 (11ꢀ-HSD2) on cortisol
using NADP as a cofactor.2 These two enzymes have very
* To whom correspondence should be addressed. Phone: 617-665-5622.
Fax: 617 665 5682. E-mail: jxiang@wyeth.com.
†
Chemical and Screening Sciences.
Drug Safety and Metabolism.
Cardiovascular and Metabolic Diseases.
‡
§
a Abbreviations: 11ꢀ-HSD1, 11ꢀ-hydroxysteroid dehydrogenase type 1;
11ꢀ-HSD2, 11ꢀ-hydroxysteroid dehydrogenase type 2; HDL, high density
lipoprotein; GR, glucocorticoid receptor; HTS, high-throughput screening;
SAR, structure-activity relationship; PK, pharmacokinetics; NADP, ꢀ-nico-
tinamide adenine dinucleotide phosphate; NADPH, ꢀ-nicotinamide adenine
dinucleotide phosphate reduced form; CHO cell, Chinese hamster ovary
cell; HLM, human liver microsomes; MLM, mouse liver microsomes.
10.1021/jm8004948 CCC: $40.75
2008 American Chemical Society
Published on Web 06/26/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14 4069
Table 2. Biological Activities of Piperazine Sulfonamides 5 and 9
Scheme 2a
IC50 (µM)
T1/2 (min)
X
Y
R1,R2
h-HSD1 m-HSD1 MLM HLM
5b
5c
5d
5e
9c
N
N
N
N
C
Cl
Cl
2, 5-trans-di-Me
2, 6-cis-di-Me
1.6
1.3
0.50
9.9
0.010
4.7
6.9
>10
>10
0.010
2
3
6
30
3
3
6
2
a Conditions: (a) Pd2(dba)3, BINAP, toluene, 80-85%; (b) TFA, CH2Cl2,
85-95%; (c) ArSO2Cl, Hunig’s base, CH2Cl2, 75-90%.
CF3 2-oxo
CF3 3-oxo
CF3 2-(R)-Me
30
5a
Scheme 3a
a Assay run in duplicate.
of analogues bearing various substitutions on the phenyl ring
will be reported in due course.
Modification of the middle piperazine ring was then under-
taken to evaluate the impact on potency and microsomal
stability. Disubstituted piperazine derivatives were prepared.
Compounds 5b and 5c showed a significant decrease in potency,
while no improvement in terms of microsomal stability was
observed (Table 2). Incorporation of a carbonyl group into
middle ring led to piperazinone analogues such as 5d and 5e.
Compound 5d is a much weaker inhibitor of the enzyme, and
no improvement in the microsomal stability was observed.
Compound 5e on the other hand has a significantly improved
microsomal stability with T1/2 > 30 min in the presence of
mouse and human liver microsomes. Unfortunately, 5e is also
drastically less potent against human and mouse 11ꢀ-HSD1.
Interestingly, analogues with monosubstitution such as 2-methyl
showed excellent activity against human and mouse 11ꢀ-HSD1.
For example, 9c has an IC50 of approximately 10 nM in cell-
based assays, which represents about 5-fold improvement in
potency against the human enzyme and 25-fold improvement
against mouse enzyme when compared to the unsubstituted
piperazine 9a. Further comparison of the 2-(R) and the 2-(S)-
methylpiperazine analogues indicated that the R series was
significantly more potent in the ex vivo assay when compared
to the S series, and we decided to focus our efforts on the R
series (data not shown). Our detailed findings on the stereo-
chemistry preference will be reported in due course.
a Conditions: (a) Pd2(dba)3, BINAP, toluene, 65-85%; (b) ArSO2Cl,
Hunig’s base, CH2Cl2, 75-90%; (c) Pd2(dba)3, BINAP, toluene, 45-75%.
Table 1. Biological Activities of Piperazine Sulfonamides 5 and 9
IC50 (µM)
T1/2 (min)
X
R
h-HSD1
m-HSD1
MLM
HLM
5a
9a
9b
N
C
C
H
H
F
0.061
0.052
0.068
0.19
0.42
0.25
5
3
8
5
4
12a
a Assay run in duplicate.
in the Buchwald amination followed by sulfonylation. 3-Sub-
stituted analogues were obtained by derivatization of bromide
12 (Scheme 3).
On the basis of the preliminary SAR of the piperazine ring
and the aryl substituent on the right-hand side of the molecule,
we focused on analogues that incorporate the 2-(R)-methylpip-
erazine in the middle ring and 2-trifluoro-4-fluorophenyl of the
right-hand side, as exemplified by 13. Further optimization of
the molecule was undertaken by focusing on the left side of
the molecule. The remainder of this communication is focused
on the meta position of the benzenesulfonamide. Analogues with
substitution at other positions offered additional opportunities
for improvement and will be published separately.
Compounds incorporating a m-piperidine (13a) or m-mor-
pholine (13b) on the benzenesulfonamide are potent inhibitors
of 11ꢀ-HSD1 with IC50 values of about 10 nM against the
human enzyme in cell-based assays. The potency of the
N-substituted piperazine analogues varies depending on the size
and the polarity of the substituents. Smaller substituents such
as 4-methyl and 4-ethyl (13c, 13d) are tolerated, while 4-iso-
propyl substitution led to a significant decrease in potency (13e).
Carbamates and ureas such as the methylcarbamate 13f and the
ethylurea 13g decreased dramatically the activity against human
11ꢀ-HSD1. Analogues containing a free amine such as 13h is
a much weaker human 11ꢀ-HSD1 inhibitor with IC50 over 10
µM. We also investigated the size of the ring at the meta position
The original hit 5a is a potent inhibitor of human and mouse
11ꢀ-HSD1 in cell-based assays (Table 1). However, 5a has low
microsomal stability with a T1/2 less than 5 min in human and
mouse liver microsomes. Pharmacokinetic studies also suggest
that 5a has very high iv clearance (149 (mL/min)/kg at 2 mg/
kg, mice) and low oral bioavailability (5% at 30 mg/kg, mice).
Metabolite studies indicated that the pyridyl ring of the molecule
is prone to oxidation. N-Dealkylation at the middle ring was
also observed. To address the oxidation of the pyridyl ring,
analogues with a phenyl ring were explored. It was very
encouraging to see that replacement of the pyridyl ring by a
phenyl ring retained activity against the enzyme. Compounds
such as 9a show potency comparable to that of the original hit
5a. However, 9a still suffers from low microsomal stability.
We then introduced a fluoro group at the phenyl ring to see if
we could block metabolic soft spots. Such analogues are easily
accessible because several fluorine-substituted o-bromotrifluo-
robenzenes are commercially available. 9b showed similar
potency to 9a, suggesting that the fluorine group is allowed at
the para position. 9b also showed improvement in microsomal
stability (T1/2 ) 12 min in the human liver microsomes versus
T1/2 ) 4 min for 9a). Detailed SAR and microsomal stability

4070 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14
Letters
Table 3. Biological Activities of 2-Methylpiperazinesulfonamides
13a-u
Table 4. Mouse Microsomal Stability, PK, and ex Vivo Data
mouse
MLM T1/2
(min)
Cl
ex vivo
((mL/min)/kg)a
Fb (%)
inhibitionc (%)
13c
13j
13n
13q
13u
15
11
>30
12
36
54
55
13
25
79
9
100
34
45
47
36
IC50 (µM)
44 (10 mpk)
38
>30
100
R
h-HSD1 m-HSD1 m-HSD1
a Mouse iv PK at 2 mg/kg in DMSO/Tween. b Mouse po PK at 30 mg/
kg in 0.5% methylcellulose/2% Tween. c 30 mg/kg po dose unless otherwise
noted.
13a
13b
13c
13d
13e
13f
13g
13h
13i
piperidine
morpholine
0.015
0.013
0.021
0.030
0.49
0.010
0.011
0.012
0.029
0.15
0.067
0.056
0.028
0.045
0.25
4-Me-piperazine
4-Et-piperazine
4-iPr-piperazine
Table 5. Rat in Vitro, PK, and ex Vivo Data
rat ex vivo
inhibition
at 2 h (%)
piperazine-4-methylcarbamate
piperazine-4-methylurea
piperazine
pyrrolidine
pyrrolidine-3-ol
0.33
0.37
>10
0.011
0.012
0.16
0.22
0.22
0.19
r-HSD1 IC50
Cmax
AUC
(µM)
(ng/mL)a
(ng·h/mL)a
0.061
0.010
0.010
0.028
0.011
0.16
0.032
0.069
0.026
0.12
0.074
0.013
0.30
0.016
0.013
0.012
0.020
0.010
0.010
0.011
0.027
0.010
0.23
0.056
0.011
0.013
0.041
0.055
0.090
0.014
0.032
0.042
0.12
13c
13j
13q
13u
0.042
0.013
0.081
0.11
246
185
149
2285
1043
1041
32
62
59
35
13j
13k
13l
pyrrolidine-3-ol (R)
pyrrolidine-3-ol (S)
9183
51088
13m pyrrolidine-3-carboxylate
a Rat po PK dosed at 30 mg/kg in 0.5% methyl cellulose/2% Tween.
13n
13o
13p
13q
13r
13s
13t
pyrrolidine-3-COOH
pyrrolidine-3-CONH2
proline
1,2,4-triazole
1,3,4-triazole
imidazole
Table 6. Effects of 11ꢀ-HSD1 Inhibitors on Cortisone Induced
Hyperinsulinemia in SD Rat
dosea (mpk, b.i.d.)
insulin reduction at day 7 (%)
0.011
0.012
0.037
0.073
0.10
13q
13c
13j
60
60
60
30
34
11
19
30
pyrazole
OCMe2COOH
13u
0.13a
a Assay run in duplicate.
13u
a Dosed po in 0.5% methyl cellulose/2% Tween.
by making five-membered rings such as the pyrrolidines.
Compound 13i is a potent inhibitor with a human IC50 of 60
nM and a mouse IC50 of 16 nM. Further SAR studies around
the pyrrolidine ring suggested that OH, CO2Et, COOH, and
amido groups are all tolerated at the 3-position (examples 13j,
13k, 13l, 13m, 13n, 13o). Proline analogues such as 13p are
also very potent, suggesting polar groups at 2-position are
tolerated. Other five-membered heterocycles such as triazole
(13q and 13r), imidazole (13s), and pyrazole (13t) are well
tolerated, yielding potent compounds against human and mouse
HSD1. These polar groups were designed to increase the
aqueous solubility of the inhibitors. In addition to N-substituted
analogues, oxygen linker analogues were also prepared. Com-
pound 13u carries a free carboxylic acid and is potent against
the mouse enzyme with an IC50 value of 37 nM. However, 13u
is weaker against the human enzyme with an IC50 value of 300
nM. It is interesting to note that for the majority of the
compounds listed in Table 3, the inhibition decreased only
marginally in the presence of serum suggesting that protein
binding of this series might not be an issue. We also note that
of all the compounds from the piperazine sulfonamide class,
none showed any activity against 11ꢀ-HSD2 at concentrations
as high as 100 µM.
Potent compounds with a microsomal stability T1/2 > 10 min
were selected for pharmacokinetics studies. Compounds 13c,
13j, 13n, 13q, and 13u have moderate iv clearance and
reasonable oral bioavailability (Table 4). For 13c, 13n, and 13u,
the oral bioavailabilities are 79-100%. These five compounds
were then tested in a mouse ex vivo assay. Compounds were
dosed orally at 30 mg/kg. Mice were sacrificed 5 h after oral
dosing. Liver samples were obtained, and the activity of 11ꢀ-
HSD1 converting cortisone to cortisol was measured. Com-
pounds 13c, 13j, and 13n showed 36-47% inhibition at 30 mg/
kg, while 13q achieved 44% inhibition at 10 mg/kg. Despite
its excellent oral bioavailability, 13u showed modest ex vivo
inhibition, which could be attributed to unfavorable tissue
distribution.
The cortisone-induced hyperinsulinemia model in rats was
one of numerous models we evaluated in the course of this
program. The aim was to determine if our 11ꢀ-HSD1 inhibitors
canpreventthecortisoneinducedhyperinsulinemiainSprague-Dawley
(SD) rats. Selected compounds were tested in CHO cell
expressing rat 11ꢀ-HSD1 to confirm their potency against the
rat enzyme. 13c, 13j, and 13q were found to be potent inhibitors
of rat 11ꢀ-HSD1 with IC50 values below 100 nM (Table 5).
PK studies were carried out to determine the plasma exposure
in rat. All of these compounds displayed reasonable exposure
with AUCs over 1000 ng·h/mL. The four compounds were
examined in the rat ex vivo assay, and 13j and 13q were the
most potent of the group tested, displaying ∼60% inhibition in
the liver.
On the basis of their favorable exposure and ex vivo
inhibition, these four compounds were tested in the rat cortisone
induced hyperinsulinemia model. Male SD rats were used for
this study. Cortisone was administered in drinking water (2 mg/
mL), and the inhibitors were dosed orally at 60 mg/kg, b.i.d.
Body weight, food intake, liquid consumption, plasma glucose,
and serum insulin were measured on day 7. After 7 days of
treatment, rats receiving 13q or 13u displayed a ∼30% decrease
in serum insulin level (Table 6, Figure 1). There was no change
in the glucose level in these animals. This finding is not
unexpected, since the model above relates to the hyperinsuline-
mia model rather than hyperglycemia.
In summary, HTS led to the identification of piperazine
sulfonamide 5a, a lead with poor microsomal stability and high
clearance. Optimization of the piperazine middle ring and the
pyridyl ring led to the identification of numerous compounds
with excellent potency, high selectivity against 11ꢀ-HSD2, and
good exposure following oral dosing. Compounds such as 13c,
13j, 13q, and 13u showed activity in the mouse and rat ex vivo
assays. We also evaluated our lead compounds in a cortisone-

Letters
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induced hyperinsulinemia model. 13q and 13u led to decreased
insulin levels after 7 days of treatment via oral administration.
Acknowledgment. We thank Drs. Nelson Huang, Li Di, and
Walter Massefski for coordinating and obtaining analytical data,
Dr. Katherine Lee for editing the manuscript, and Dr. Steve
Tam for his scientific input.
Supporting Information Available: Experimental details for
the synthesis and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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